KR20220093330A - Combination of CXCR7 antagonist and S1P1 receptor modulator - Google Patents

Abstract

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및 CXCR7 발현 또는 그것의 리간드 및 S1P 둘 모두가 역할을 하는 질환 및 장애의 예방 또는 치료에 있어서, 특히 스핑고신-1-포스페이트 수용체 1 조절인자 (S1P1 수용체 조절인자) 를 포함하는 다른 활성 성분 또는 치료제와의 조합으로의, CXCL11/CXCL12 수용체 CXCR7 의 조절인자로서의 그것의 용도에 관한 것이다. 본 발명은 또한 상기 다른 활성 성분(들) 또는 치료제(들)과의 조합으로 COMPOUND 를 포함하는 약학적 조성물에 관한 것이다.The present invention relates to the compound (3S,4S)-1-cyclopropylmethyl-4-{[5-(2,4-difluoro-phenyl)-isoxazole-3-carbonyl]-amino}-piperidine- 3-carboxylic acid (1-pyrimidin-2-yl-cyclopropyl)-amide:

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and other active ingredients or therapeutic agents, including especially sphingosine-1-phosphate receptor 1 modulators (S1P1 receptor modulators) for the prevention or treatment of diseases and disorders in which CXCR7 expression or its ligand and S1P both play a role to its use as a modulator of the CXCL11/CXCL12 receptor CXCR7 in combination with The present invention also relates to pharmaceutical compositions comprising COMPOUND in combination with said other active ingredient(s) or therapeutic agent(s).

Description

Combination of CXCR7 antagonist and S1P1 receptor modulator

The present invention relates to the compound (3S,4S)-1-cyclopropylmethyl-4-{[5-(2,4-difluoro-phenyl)-isoxazole-3-carbonyl]-amino}-piperidine- 3-carboxylic acid (1-pyrimidin-2-yl-cyclopropyl)-amide (hereinafter also referred to as “COMPOUND”):

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and other active ingredients comprising a sphingosine-1-phosphate receptor 1 modulator (S1P1 receptor modulator) for the prevention/prevention or treatment of diseases and disorders in which CXCR7 expression or its ligand and S1P both play a role or to its use as a modulator of the CXCL11/CXCL12 receptor CXCR7 in combination with therapeutic agents. The present invention also relates to pharmaceutical compositions comprising COMPOUND in combination with said other active ingredient(s) or therapeutic agent(s). The present invention also relates to a COMPOUND of a daily dose that can be well tolerated and pharmaceutically effective when administered once or twice daily in the prevention/prevention or treatment of diseases and disorders in which CXCR7 expression or its ligand plays a role. is about

COMPOUND is known from WO2018/019929 as a modulator of the CXCL11/CXCL12 receptor CXCR7. The crystalline form of COMPOUND is known from WO2019/145460. COMPOUND may potentially be used in the prevention/prevention or treatment of certain diseases and disorders related to the CXCR7 receptor or its ligands, including:

• cancers such as malignant gliomas, brain tumors including glioblastoma multiforme; neuroblastoma; pancreatic cancer, including pancreatic adenocarcinoma/pancreatic adenocarcinoma; gastrointestinal cancers including colon carcinoma, hepatocellular carcinoma and gastric cancer; Kaposi's sarcoma; leukemia, including adult T-cell leukemia; lymphoma; lung cancer; breast cancer; rhabdomyosarcoma; prostate cancer; esophageal squamous cell carcinoma; oral squamous cell carcinoma; endometrial cancer; thyroid carcinoma, including papillary thyroid carcinoma; metastatic cancer; lung metastases; skin cancer, including melanoma and metastatic melanoma; bladder cancer; multiple myeloma; osteosarcoma; head and neck cancer; and renal carcinoma, including renal clear cell carcinoma, metastatic renal clear cell carcinoma;

inflammatory diseases such as chronic rhinosinusitis, asthma, chronic obstructive pulmonary disorder, atherosclerosis, myocarditis, acute lung injury, endometriosis, uveitis, diabetic retinopathy and sarcoidosis;

• autoimmune disorders such as (inflammatory) demyelinizing disease; multiple sclerosis (MS); Guillain-Barré Syndrome; rheumatoid arthritis (RA); inflammatory bowel disease (including IBD, particularly Crohn's disease and ulcerative colitis); systemic lupus erythematosus (SLE), including neuropsychiatric systemic lupus erythematosus and lupus nephritis; interstitial cystitis; celiac disease; autoimmune encephalomyelitis; osteoarthritis; type I diabetes; psoriasis; autoimmune thyroiditis; Sjogren's syndrome; ankylosing spondylitis and vitiligo;

• neurodegenerative disorders such as amyotrophic lateral sclerosis;

• transplant rejection (particularly renal allograft rejection, cardiac allograft rejection, and graft versus host disease caused by hematopoietic stem cell transplantation);

• Fibrosis (especially liver fibrosis, liver cirrhosis, pulmonary fibrosis, cardiac fibrosis, especially idiopathic pulmonary fibrosis); and

• ischemic damage such as renal ischemia or cerebral ischemia.

Chemokine receptors are a group of G-protein coupled receptors (GPCRs) that bind with high affinity to peptidic chemokine ligands. Although the main function of chemokine receptors is to induce leukocyte trafficking to organs and tissues of the lymphatic system during inflammation as well as under resting conditions, a role for specific chemokine receptors on non-hematopoietic cells and their progenitors has also been recognized.

CXCR7 (alias ACKR3, alias RDC1, alias CMKOR1, alias GPR159) has two known chemokine ligands: CXCL12 (alias stromal cell-derived factor 1, SDF-1; alias Pre-B cell growth stimulatory factor, PBSF) and CXCL11 (alias l-TAC, alias IFN-g-inducible T cell chemoattractant). Binding of CXCL11 or CXCL12 to CXCR7 results in internalization of the CXCR7-ligand complex (Burns JM et al. J Exp Med 2006, 203(9):2201-13) and degradation of the ligand (Naumann U et al. PLoS One 2010, 5). (2):e9175). This scavenging activity contributes to the establishment and maintenance of gradients of CXCL11 and CXCL12 concentrations from blood vessels to tissues.

CXCL12, an epilepsy-derived chemoattractant, participates in immune surveillance and modulation of inflammatory responses. CXCL12 is secreted by bone marrow stromal cells, endothelial cells, heart, skeletal muscle, liver, brain, kidney, thymus, lymph nodes, parenchymal cells, and plays an essential role in stem cell proliferation, survival, and homing of hematopoietic/progenitor cells to the bone marrow. (Rankin SM et al.; Immunol let. 2012, 145(1-2):47-54). CXCL12 is induced under certain pathological disorders including ischemia, inflammation, hypoxia, cancer, neurodegenerative diseases and autoimmune diseases (Juarez J et al. Curr Pharm Des 2004, 10(11): 1245-59).

CXCL12 also recruits bone marrow-derived progenitor cells to the site of vasculature. Besides, it also plays an important role in carcinogenesis. CXCL12 promotes recruitment of endothelial progenitor cells and bone marrow-derived suppressor cells as well as other bone marrow-derived cells to the tumor site. CXCL12 also plays a role in cell migration, adhesion and survival during inflammation (Kumar R et al. Cell Immunol. 2012, 272(2):230-41). CXCL12 also induces differentiation and maturation of cells such as oligodendrocyte progenitor cells (Gottle P et al. Ann Neurol. 2010, 68(6):915-24).

CXCL11 is mainly expressed in the pancreas, peripheral blood leukocytes, thymus, liver, spleen and lungs. This chemokine is induced by interferon and is upregulated during infection or cancer processes (Cole et al. J Exp Med. 1998, 187(12):2009-21).

In addition to CXCR7, CXCL12 is CXCR4 (alias fussin, alias leukocyte-derived 7-transmembrane-domain receptor; LESTR, alias D2S201E, alias 7-transmembrane-segment receptor, alias HM89, alias lipopolysaccharide-associated protein 3; lap3, Alias LPS-associated protein 3) binds and activates, whereas CXCL11 binds to and activates CXCR3 (alias GPR9, alias CD183).

The interaction of CXCR7 and its ligands CXCL12 and CXCL11 (hereinafter referred to as the CXCR7 axis) is thus involved in directing receptor bearing cells to specific places in the body, particularly sites of inflammation, immune damage and immune dysfunction, and also tissue It is associated with injury, induction of apoptosis, cell growth and angiogenesis. CXCR7 and its ligands are upregulated and highly expressed in a variety of pathological conditions, including cancer, autoimmune disorders, inflammation, infection, transplant rejection, fibrosis and neurodegeneration.

CXCR7 modulators, alone or in combination, modulate CXCR7 (e.g. using siRNA, shRNA, microRNAs, overexpression, CXCR7 knockout animals, CXCR7 agonists, CXCR7 antagonists, antibodies or Nanobodies) to regulate this leukocyte migration and (Berahovich RD et al.; Immunology. 2014, 141(1):111-22) found to promote myelin/neuron repair (Williams JL et al.; J Exp Med. 2014, 5; 211(5):791) -9; Gottle P et al.; Ann Neurol. 2010, 68(6):915-24) disease, multiple sclerosis and autoimmune encephalomyelitis (Cruz-Orengo L et al.; J Neuroinflammation. 2011, 6; 8:170; Bao J et al.; Biochem Biophys Res Commun. 2016 Jan 1; 469(1):1-7), Guillain-Barré syndrome or autoimmune neuritis (Brunn A et al.; Neuropathol Appl Neurobiol. 2013 , 39(7):772-87), and experimental diseases of inflammatory, autoimmune and demyelinated diseases, including rheumatoid arthritis (Watanabe K et al.; Arthritis Rheum. 2010, 62(11):3211-20). It has been shown to provide beneficial effects in the model.

Specifically, the effect of CXCR7 on inflammatory demyelination disease is known from the literature. CXCR7 is expressed in various regions throughout the adult mouse brain, and its expression is upregulated during demyelination in a mouse model for multiple sclerosis (MS) and in a non-inflammatory demyelination model (Banisadr G et al.; J Neuroinflammation). Pharmacol. 2016 Mar; 11(1):26-35; Williams JL et al.; J Exp Med. 2014, 5; 211(5):791-9; Gottle P et al.; Ann Neurol. 2010, 68 ( 6):915-24). The altered expression pattern of CXCL12 at the blood-brain barrier (BBB) is implicated in multiple sclerosis and correlates with disease severity (McCandless EE et al.; Am J Pathol. 2008, 172(3):799-808). ). CXCR7 functional antagonism has been shown to be effective against experimental autoimmune encephalomyelitis in mice. These recent studies strongly suggest CXCR7 as a disease-modifying molecule in multiple sclerosis through a complementary mechanism by: (i) promoting leukocyte influx into the perivascular space via CXCL12 redistribution at the BBB (Cruz-Orengo) L et al.; J Neuroinflammation. 2011, 6; 8:170; Cruz-Orengo L et al.; J Exp Med. 2011, 14; 208(2):327-39) by modulating CXCR4-mediated activation of integrins. (Hartmann TN et al.; J Leukoc Biol. 2008,; 84(4):1130-40) (ii) for microglia chemotaxis (Bao J et al.; Biochem Biophys Res Commun. 2016 Jan 1; 469 (1):1-7) and direct effects on inflammatory monocytes, by facilitating their entry into the brain (Douglas SD et al.; J Leukoc Biol. 2017; 102:1155-1157) (iii) CXCR4 -by promoting remyelination through increased levels of CXCL12 which promotes mediated oligodendrocyte progenitor cell maturation (Williams JL et al.; J Exp Med. 2014, 5; 211(5):791-9; Gottle P et al.; Ann Neurol. 2010, 68(6):915-24). Recently, Chu et al. (Neuroscientist. 2017, 23(6): 627-648) reported that CXCL12 for demyelination disease due to their central role in promoting migration, proliferation and differentiation of oligodendrocyte progenitors. The importance of targeting the /CXCR4/CXCR7 axis was reviewed. Therefore, CXCR7 antagonism can therapeutically prevent inflammation and enhance myelination repair in demyelinated adult CNS.

Specifically, the potential role of CXCR7 in rheumatoid arthritis is known from the literature. CXCR7 is reported to be expressed in endothelial cells in the synovial membrane. In addition, elevated levels of CXCL12 and CXCL11 mRNA were found in the synovial tissue of rheumatoid arthritis patients (Ueno et al.; Rheumatol Int. 2005, 25(5):361-7). CXCL12 has been shown to play a central role in CD4 ⁺ T cell and monocyte accumulation in the synovial membrane (Nanki T et al.; J Immunol. 2000, 165(11):6590-8; Blades MC et al.; Arthritis Rheum. 2002 Mar; 46(3):824-36). In addition, CXCL12 participates in the rheumatoid arthritis process through its pro-angiogenic function and its action on osteoclast recruitment and differentiation. Therefore, modulators of the CXCL12 pathway, including the CXCR7 modulator, have been proposed as potential therapeutic agents for the treatment of rheumatoid arthritis. Villalvilla et al. (Expert Opin Ther Targets. 2014, 18(9):1077-87) recently discussed preclinical and clinical data supporting the potential use of anti-CXCL12 agents in the treatment of rheumatoid arthritis. Watanabe et al. (Arthritis Rheum. 2010, 62(11):3211-20) demonstrated that CXCR7 inhibitors prophylactically and therapeutically reduce disease clinical signs and angiogenesis in a mouse collagen-induced arthritis model.

CXCR7 is further reported to be involved in acute and chronic pulmonary inflammatory processes such as chronic obstructive pulmonary disease, acute lung injury, asthma, pulmonary inflammation, pulmonary fibrosis, as well as several inflammatory disorders including atherosclerosis, liver fibrosis, and cardiac fibrosis. do.

CXCL12 and CXCL11 are also reported to be upregulated in inflammatory bowel disease (Koelink PJ et al.; Pharmacol Ther. 2012, 133(1):1-18). CXCR7 has been shown to be upregulated on peripheral blood T cells in inflammatory bowel disease (IBD) (Werner L et al.; J Leukoc Biol. 2011, 90(3):583-90). The authors hypothesized that "increased expression of CXCR7 in the peripheral blood of IBD patients may promote increased influx of T cells to sites of mucosal inflammation" (Werner L et al.; Theranostics. 2013, 3(1)). :40-6). In a mouse model of IBD, modulators of the CXCL12 pathway can reduce T cell infiltration and reduce tissue damage (Mikami S et al.; J Pharmacol Exp Ther. 2008, 327(2):383-92; Xia XM et al.; PLoS One. 2011, 6(11):e27282).

Elevated levels of CXCL12 and CXCL11 have also been found in lesional psoriatic skin (Chen SC et al.; Arch Dermatol Res. 2010, 302(2):113-23; Zgraggen S et al.; PLoS One. 2014, 9 (4):e93665). Zgraggen et al. demonstrated that blockade of CXCL12 ameliorated the course of chronic skin inflammation in two different models of psoriasis-like skin inflammation.

Several other autoimmune disorders, such as systemic lupus erythematosus (SLE), exhibit altered CXCR7/CXCR4 expression that correlates with impaired CXCL12-promoted migration of SLE B cells (Biajoux V et al.; J Transl Med. 2012, 18 ; 10:251). In addition, CXCL12 was significantly upregulated in renal kidney in a multiple murine model of lupus. Wang et al. (J Immunol. 2009, 182(7):4448-58) found that acting on the CXCL12 axis in lupus because CXCR4 antagonists markedly ameliorate disease, prolong survival, and reduce nephritis and lymphoproliferative. It has been shown to be a good therapeutic target.

Matin et al. (Immunology. 2002, 107(2):222-32) demonstrated that blockade of CXCL12 by an antibody resulted in a reduction in the incidence of diabetes and inhibition of insulin salt in a diabetic mouse model.

CXCL12 and CXCR4 have been shown to be upregulated in thyroid and animal models from autoimmune patients (Armengol MP et al.; J Immunol. 2003, 170(12):6320-8). Liu et al. (Mol Med Rep. 2016, 13(4):3604-12) disclose that blockade of CXCR4 reduces the severity of autoimmune thyroiditis in mice, thereby reducing lymphocyte infiltration and autoantibody production.

CXCR4 was found to be upregulated in synovial tissue from ankylosing spondylitis patients (He C et al.; Mol Med Rep. 2019, 19(4):3237-3246). CXCR4 inhibition reduced fibroblast proliferation and bone formation.

Neurodegenerative disorders have been found to exhibit altered CXCL12/CXCR4 expression. This pathway is involved in the recruitment and differentiation of self-renewing and pluripotent neural progenitor cells that play important roles during tissue repair. Meizhang et al. reviewed the role of CXCL12 in neurodegenerative diseases and the impact of manipulation of the CXCL12 signaling pathway on neurodegenerative disorders in animal models (Meizhang et al. Trends Neurosci. 2012, 35(10): 619-628). Recently, the expression of CXCL12 and CXCR4 was found to be upregulated in the peripheral blood of patients with Parkinson's disease (Bagheri et al. Neuroimmunomodulation. 2018, 25(4):201-205). The CXCR4/CXCL12 pathway has also been implicated in inflammatory processes occurring in Alzheimer's disease (Hongyan et al. Brain Circ. 2017, 3(4):199-203). Rabinovich-Nikitin et al. reported that blocking CXCR4/CXCL12 signaling reduces microglia inflammation, reduces blood-brain barrier permeability, increases the number of motor neurons, and prevents survival of mice in the amyotrophic lateral sclerosis (ALS) model. teach to increase (Rabinovich-Nikitin et al. J Neuroinflammation. 2016, 13: 123).

CXCR7 is also known as a scavenger receptor for several opioid peptides, particularly enkephalins and dinorphins, and modulates their availability and thereby signaling through their classical opioid receptors (Meyrath M et al. Nat Commun. 2020;11(1):3033). As CXCR7 acts as a broad-spectrum scavenger for opioid peptides, administration of CXCR7 antagonists can induce an increase in these opioid peptides similar to the increase observed for the chemokine ligands CXCL11 and CXCL12. As such, modulation of endogenous opioid levels can be used for clinical pain management and modulation of nociception (Holden JE et al. AACN Clin Issues. 2005; 16(3): 291-301). Since cerebrospinal fluid levels of prodinorphine-derived peptides that have been shown to bind to CXCR7 are decreased in patients with Huntington's disease (Al Shweiki MR et al. Mov Disord. 2020; doi: 10.1002/mds.28300), these peptides by administration of CXCR7 antagonists Increasing the level of may be beneficial in this disease. Endogenous opioid peptides are also implicated in mood disorders such as depression (Peciρa M et al. Mol Psychiatry. 2019; 24(4): 576-587). Therefore, it can be expected that modulating endogenous peptide levels by blocking the scavenging receptor CXCR7 could be used to treat mood disorders. Along the way, CXCR7 modulators have been shown to have anti-anxiety activity in preclinical models (Ikeda Y et al. Cell. 2013; 155(6): 1323-36). Therefore, CXCR7 modulators, in addition to the diseases and disorders related to the CXCR7 receptor or its ligands mentioned above, are opioid receptor signaling including neuropathic pain, neurodegenerative diseases such as Huntington's disease, addiction disorders, mood disorders, anxiety disorders. It may be useful for the prevention/prevention or treatment of certain diseases and disorders associated with delivery.

Several sphingosine-1-phosphate receptor 1 modulators (alternatively termed S1P1 receptor modulators, non-selective S1P1 receptor modulators such as fingolimod, as well as selective S1P1 receptor modulators) act on the S1P1 receptor. It is an S1P1 receptor agonist that acts pharmacologically as a sexual antagonist. S1P1 receptor modulators have been described as useful for the prevention and/or treatment of diseases or disorders associated with an activated immune system (Juif et al., Exp. Op. Drug Metabol. & Tox. (2016) 12(8), 879- 895). S1P1 receptor modulators indirectly antagonize the function of S1P1 receptors and sequestration of lymphocytes from lymph nodes (Subei et al, CNS Drugs. 2015 Jul; 29(7): 565-575). It was confirmed that multiple S1P1 receptor modulators signal through S1P1 in the same way to induce S1P1 receptor degradation (Lukas et al., J. Biomol. Screening (2014) 19(3) 407-416). In clinical practice, S1P1 receptor modulators, including non-selective and selective S1P1 receptor modulators, represent a risk for bradyarrhythmias and atrial blockade (AV block). As a result, it is recommended that heart rate and blood pressure be generally monitored during the initiation of a patient's treatment, for example in the case of fingolimod. Mitigation of the risk of using up-titration dosing regimens has been proposed and such dosing regimens are being used in clinical practice (eg for fingolimod: WO2006/058316, WO2010/075239, WO2011/041145, WO2013/055833; po for nesimod: see WO2009/115954, WO2016/091996; for siphonimod: see WO2010/072703, WO2013/057212, WO2015/155709). Another potential trend for certain S1P1 receptor modulators that are available or under development is that treatment generally induces lymphopenia, and in certain cases may lead to severe lymphopenia associated with an increased risk of infection. Combinations with other active ingredients could result in increased potency and/or the presence of a higher lymphocyte count. In addition, the combination with other active ingredients could allow a reduction in the minimum effective dose of S1P1 receptor modulators. Thus, such a combination with other active ingredients may be advantageous, especially when the immune system needs to be reactivated, for example in an emergency, such as an acute infection.

S1P1 receptor modulators have been described as having a unique mechanism of action, particularly in the treatment of multiple sclerosis (MS) (Chaudhry et al. Neurotherapeutics (2017) 14:859-873). MS is a chronic inflammatory and demyelinated disease of the CNS in which the inflammatory process is associated with destruction of myelin leading to the appearance of large focal lesions of demyelination. Axonal damage and loss as a result of inflammatory demyelination also occurs to a variable extent. Active remyelination processes can at least partially restore myelin lesions, whereas axonal loss is permanent and irreversible. MS is primarily considered an autoimmune neurodegenerative disease, ie a disease caused by an adaptive immune response to autoantigens. In MS, activated myelin-responsive T cells are recruited from the periphery to the CNS, leading to activation of microglia and recruitment of circulating macrophages (Grassi et al. Frontiers in Pharmacology 2019, doi:10.3389/fphar.2019.00807) .

S1P1 receptor modulators have potential use in neurodegenerative diseases where S1P1 receptor modulators directly affect CNS resident cells such as microglia, astrocytes, neurons, oligodendrocyte progenitors and oligodendrocytes ( Miron et al. J Neurol Sci. 2008, 274(1-2):13-7), have been disclosed to provide beneficial effects in experimental disease models of neurodegeneration.

Specifically, the effect of S1P on neurodegenerative diseases is known from the literature. Yazdi et al. recently discussed experimental and clinical studies supporting the direct effect of S1P1 receptor modulators on myelination (Yazdi et al. J Neuro Res. 2019, 00:1-13). Angelopoulou et al. recently reviewed the involvement of S1P in the pathogenesis of Alzheimer's disease (AD) and the beneficial effects of S1P1 receptor modulators in the AD model (Angelopoulou et al. Neuromolecular Med. 2019, 21(3):227-238). . It has been shown that S1P1 receptor modulators can modulate neuroinflammatory responses and increase the expression of brain-derived neurotrophic factors in a model of amyotrophic lateral sclerosis (ALS), thereby reducing neurological deficits and prolonging the survival of mice ( Potenza et al. Neurotherapeutics. 2016, 13(4): 918-927). Miguez et al. teach that S1P1 receptor modulators improve hippocampal synaptic plasticity and memory in a mouse model of Huntington's disease, thereby reducing astrocytes and reducing local inflammation (Miguez et al. Hum Mol Genet. 2015, 24(17)). :4958-70).

fingolimod (2-amino-2-[2-(4-octylphenyl)ethyl]-propane-1,3-diol, CAS Reg. No. 162359-55-9, for example WO2008/000419, WO2010/ 055027, WO2010/055028, WO2010/072703) are non-selective S1P1 receptor modulators indicated for the treatment of relapsing multiple sclerosis (MS). Fingolimod 0.5 mg once daily is the first oral therapy approved for relapsing multiple sclerosis in many countries and for highly active relapsing MS (RRMS) in the European Union. In the United States, fingolimod is indicated for the treatment of relapsing multiple sclerosis (MS), including clinical solitary syndrome, relapsing-remitting disease, and active secondary progressive disease in patients 10 years of age or older, and adults weighing more than 40 kg. and the recommended dosage for pediatric patients is 0.5 mg orally once daily. Fingolimod has pharmacodynamic effects, including reduced lymphocyte counts, that remain in the blood for up to 2 months after the last administration of fingolimod. Lymphocyte counts usually return to normal within 1 to 2 months after discontinuation of treatment. Although long wash-out periods were observed, it has also been shown that reducing the dose of fingolimod, for example to 0.5 mg every other day, can result in disease reactivation in a significant proportion of patients ( Zecca et al., Multiple Sclerosis Journal (2017) 24(2), 167-174).

fonesimod [(R)-5-[3-chloro-4-(2,3-dihydroxy-propoxy)-benz[ Z ]ylidene]-2-([ Z ]-propylimino)- 3-o-Tolyl-thiazolidin-4-one, CAS Reg. No. 854107-55-4, for example WO2005/054215, WO2008/062376, WO2010/046835, WO2014/027330] is a selective S1P1 receptor agonist whose oral administration is a consistent and sustained dose- leads to a decrease in dependence. Fonesimod has been described as useful for the treatment and/or prevention of diseases or disorders associated with an activated immune system (see, eg, WO 2005/054215 and WO 2009/115954). In particular, ponesimod showed clinical benefit in phase II/III trials in patients with moderate to severe chronic plaque psoriasis and relapsing-remitting multiple sclerosis. Ponesimod can be prepared according to the procedures disclosed in WO 2005/054215, WO 2008/062376 and WO 2014/027330.

senerimod [(S)-3-[[4-[5-(2-cyclopentyl-6-methoxypyridin-4-yl)[1,2,4]oxadiazol-3-yl]-2 -Ethyl-6-methylphenyl]-oxy]-propane-1,2-diol, CAS Reg. No. 1262414-04-9, for example WO2011/007324, WO2013/175397, WO2016/184939, Piali et al., Pharmacol Res Perspect. 2017;e00370] is a selective S1P1 receptor agonist and has entered a multi-dose efficacy and safety study for the treatment of systemic lupus erythematosus. It appears that no up-titration dosing regimen is required for senerimod.

Cyponimod (1-(4-[1-[(E)-4-Cyclohelyl-3-trifluoromethyl-benzyloxyimino]-ethyl]-2-ethyl-benzyl)-azetidine-3-carboxylic acid , CAS Reg. No. 1230487-00-9, for example WO2004/103306, WO2010/071794, WO2010/080409, WO2010/080455, WO2019/064184) are S1P1 receptor modulators and multiple sclerosis that occurs independent of acute recurrence It has been studied for the treatment of secondary progressive multiple sclerosis (SPMS), a progressive neurological decline of In active SPMS, siphonimod reduces the risk of disability and MS recurrence. In the United States, siphonimod is a clinical solitary syndrome (defined as the first episode of neurological symptoms lasting at least 24 h and caused by inflammation or demyelination in the central nervous system) in adults, relapsing disease, and active secondary progressive disease. It is indicated for the treatment of relapsing multiple sclerosis (MS), including (SPMS), and the recommended maintenance dose is 2 mg orally once daily. After discontinuation of siphonimod therapy, siphonimod remains in the blood for up to 10 days. Initiating other therapies during this period will result in concurrent exposure to siphonimod. Lymphocyte counts returned to normal in 90% of patients within 10 days of discontinuation of therapy. However, residual pharmacodynamic effects, such as lowering effects on peripheral lymphocyte count, may persist up to 3-4 weeks after the last administration. Use of immunosuppressive agents within this period may result in additive effects on the immune system, and therefore caution should be exercised 3-4 weeks after the last administration of siphonimod.

ozanimod (5-[3-[(1S)-2,3-dihydro-1-[(2-hydroxyethyl)amino]-1H-inden-4-yl]-1,2,4-oxa Diazol-5-yl]-2-(1-methylethoxy)-benzonitrile, CAS Reg. No. 1306760-87-1, for example WO2011/060392, WO2015/066515, WO2018/184185, WO2018/208855 , WO2018/215807, WO2019/058290, WO2019/094409) is an investigational S1P1 receptor modulator tested in a phase III clinical trial (NCT02047734) for the treatment of relapsing multiple sclerosis (RMS); It is further tested in Crohn's disease and ulcerative colitis (UC). Since 2020, ozanimod has been indicated for the treatment of relapsing multiple sclerosis (MS), including clinical solitary syndrome, relapsing-remitting disease, and active secondary progressive disease, in adults in the United States; and in Europe indicated for the treatment of adult patients with relapsing-remitting multiple sclerosis (RRMS) with active disease as defined by clinical or imaging features.

ettrasimod [(3R)-7-[[4-cyclopentyl-3-(trifluoromethyl)phenyl]methoxy]-1,2,3,4-tetrahydrocyclopent[b]indole-3- Acetic acid, CAS Reg. No. 1206123-37-6, for example WO2010/011316, WO2011/094008, WO2016/112075, WO2016/209809, Al-Shamma et al, J Pharmacol Exp Ther (2019) 369:311-317] is for example Crohn's disease and an investigational S1P1 receptor modulator currently under development for the treatment of inflammatory bowel diseases including ulcerative colitis (UC).

Additional S1P1 receptor modulators have been described and tested clinically, but their development may have been halted:

Amicellimod (MT-1303, 2-amino-2-[2-[4-(heptyloxy)-3-(trifluoromethyl)phenyl]ethyl]-1,3-propanediol, CAS Reg. 942399-20-4, for example WO2007/069712, WO2018/021517; Harada et al., Br J Clin Pharmacol (2017) 83 1011-1027; Sugahara et al., Br.J.Pharmacol. (2017) 174 15 -27);

Seralipimod (1-[[3,4-dihydro-6-[(2-methoxy-4-propylphenyl)methoxy]-1-methyl-2-naphthalenyl]methyl]-3-ase tidinecarboxylic acid, CAS Reg. No. 891859-12-4, eg WO2006/064757, Kurata et al. JMedChem 60(23) (2017), 9508-9530);

GSK 2018682 (4-[5-[5-chloro-6-(1-methylethoxy)-3-pyridyl]-1,2,4-oxadiazol-3-yl]-1H-indole-1- butanoic acid, eg WO2008/074821);

CS-0777 (1-[5-[(3R)-3-amino-4-hydroxy-3-methylbutyl]-1-methyl-1H-pyrrol-2-yl]-4-(4-methylphenyl)- 1-butanone, CAS Reg. No. 827344-05-8, eg WO2005/079788, Nishi et al., Med Chem Lett. 2011 2;2(5):368-72); and

Mokrabimod (2-amino-2-[2-(2-chloro-4-{[3-(phenylmethoxy)phenyl]sulfanyl}phenyl)ethyl]propane-1,3-diol; KEP203, CAS Reg No. 509092-16-4, eg US 9,920,005, US 6,960,692) has been disclosed to enter the study of high-risk acute myeloid leukemia.

COMPOUND, a CXCR7 antagonist with potential in the prevention/prevention and treatment of diseases and disorders responsive to activation of the CXCL12 receptor and/or CXCL11 receptor, is a component of an inflammatory autoimmune response, and/or a component of a neurodegenerative response; It has been found that it can have complementary and even synergistic effects when combined with S1P1 receptor modulators in the treatment of disorders. Thus, such combinations are particularly effective in autoimmune and inflammatory diseases and disorders, transplant rejection, and neurodegenerative diseases and disorders (particularly autoimmune diseases and disorders with an inflammatory component, in particular autoimmune and/or inflammatory demyelination, including multiple sclerosis). sexually transmitted diseases and disorders). In addition, the potential remyelination pharmacological effect of COMPOUND may complement the S1P1 receptor modulator, a clinically established treatment option for these inflammatory demyelination diseases. Moreover, the combination of COMPOUND and an S1P1 receptor modulator may tolerate a reduction in the dose of the corresponding S1P1 receptor modulator, potentially even at doses below the established optimal effective dose of this S1P1 receptor modulator when administered alone. , and therefore, potentially certain safety risks known to be associated with certain S1P1 receptor modulators [e.g. effects on the cardiovascular system (bradycardia), and/or after discontinuation of treatment in situations where exposure to S1P1 receptor modulators is contraindicated. long residual exposure, and/or (potentially severe) lymphopenia].

1 shows the dose-dependent effect of COMPOUND on the overall severity of EAE disease as assessed by the cumulative disease score.
2 shows the dose-dependent effect of COMPOUND on CXCL12 plasma concentrations in a mouse MOG-induced EAE model.
3 shows the effect of fingolimod (0.03 mg/kg, qd) on the overall severity of EAE disease as assessed by the cumulative disease score.
4 shows the therapeutic efficacy of COMPOUND, fingolimod, and combinations thereof on mean clinical score in an EAE mouse model.
5 shows the therapeutic effect of COMPOUND, fingolimod, and combinations thereof on the severity of EAE disease in mice presented as maximal clinical score.
6 shows the therapeutic effect of COMPOUND, fingolimod, and combinations thereof on neurofilament light chain plasma concentrations in a mouse EAE model.
7 shows the effect of COMPOUND, fingolimod, and combinations thereof on blood lymphocyte count in a mouse EAE model.
8 shows the effect of COMPOUND, fingolimod, and combinations thereof on plasma CXCL12 concentrations in a mouse EAE model.
9 shows the direct effect of COMPOUND on myelination confirmed in the cuprizone-induced demyelination mouse model.
10 shows the effect of COMPOUND on the number of mature oligodendrocytes in a cuprizone-induced demyelination mouse model.
11 shows the therapeutic effect of COMPOUND or fingolimod starting 1 week before cuprizone withdrawal on demyelination/remyelination in a mouse cuprizone-induced demyelination model.
12 shows the dose-dependent effect of COMPOUND on the overall severity of EAE disease as assessed by the cumulative disease score.
13 shows a dose-dependent effect of COMPOUND on plasma CXCL12 concentrations in a mouse PLP-induced EAE model.
14 shows the dose-response relationship of peak CXCL12 plasma concentrations after a single dose in healthy human subjects.
15 shows the predicted exposure response relationship at steady state stratified by dose.

DETAILED DESCRIPTION OF THE INVENTION

1) The first embodiment comprises, as an active ingredient, COMPOUND, or a pharmaceutically acceptable salt thereof, in combination with an S1P1 receptor modulator, or a pharmaceutically acceptable salt thereof, as well as at least one pharmaceutically acceptable salt. It relates to a pharmaceutical composition comprising an acceptable (inert) excipient.

The pharmaceutical composition according to embodiment 1) can be used as a medicament, for example in the form of a pharmaceutical composition for enteral (especially oral) or parenteral administration (including topical application or inhalation).

2) A further embodiment relates to the pharmaceutical composition according to embodiment 1), wherein the S1P1 receptor modulator is fingolimod, ponesimod, siphonimod, ozanimod, senerimod, etracimod , amicelimod, seralifimod, GSK 2018682, or CS-0777; or, furthermore, mokrabimod (in particular fingolimod, ponesimod, siphonimod, or ozanimod; or, furthermore, senerimod); or a pharmaceutically acceptable salt thereof.

3) A further embodiment relates to the pharmaceutical composition according to embodiment 1), wherein the S1P1 receptor modulator, or a pharmaceutically acceptable salt thereof, is fingolimod, ponesimod, siphonimod, ozani mod, senerimod, or etrasimod (especially fingolimod, ponesimod, siphonimod, or ozanimod), or a pharmaceutically acceptable salt thereof.

4) A further embodiment relates to the pharmaceutical composition according to embodiment 1), wherein the S1P1 receptor modulator, or a pharmaceutically acceptable salt thereof, is senerimod, etracemod, or amicelimod (in particular senerimod or etracemod), or a pharmaceutically acceptable salt thereof.

5) A further embodiment relates to the pharmaceutical composition according to embodiment 1), wherein the S1P1 receptor modulator, or a pharmaceutically acceptable salt thereof, is fingolimod, or a pharmaceutically acceptable salt thereof.

6) A further embodiment relates to the pharmaceutical composition according to embodiment 1), wherein the S1P1 receptor modulator, or a pharmaceutically acceptable salt thereof, is fonesimod, or a pharmaceutically acceptable salt thereof.

7) A further embodiment relates to the pharmaceutical composition according to embodiment 1), wherein the S1P1 receptor modulator, or a pharmaceutically acceptable salt thereof, is siphonimod, or a pharmaceutically acceptable salt thereof.

8) A further embodiment relates to the pharmaceutical composition according to embodiment 1), wherein the S1P1 receptor modulator, or a pharmaceutically acceptable salt thereof, is ozanimod, or a pharmaceutically acceptable salt thereof.

9) A further embodiment relates to the pharmaceutical composition according to embodiment 1), wherein the S1P1 receptor modulator, or a pharmaceutically acceptable salt thereof, is senerimod, or a pharmaceutically acceptable salt thereof.

10) A further embodiment relates to the pharmaceutical composition according to embodiment 1), wherein the S1P1 receptor modulator, or a pharmaceutically acceptable salt thereof, is etracimod, or a pharmaceutically acceptable salt thereof.

11) A further embodiment relates to the pharmaceutical composition according to embodiment 1), wherein the S1P1 receptor modulator, or a pharmaceutically acceptable salt thereof, is amicelimod, or a pharmaceutically acceptable salt thereof.

12) A further embodiment relates to the pharmaceutical composition according to any one of embodiments 1) to 11), wherein the S1P1 receptor modulator, or a pharmaceutically acceptable salt thereof, is an oral compound of the S1P1 receptor modulator. included in a pharmaceutical dosage form suitable for administration,

fingolimod, or a pharmaceutically acceptable salt thereof, if present, is included in said pharmaceutical dosage form in a unit dose suitable for oral administration of fingolimod up to about 0.5 mg/day in total;

• siphonimod, or a pharmaceutically acceptable salt thereof, if present, is included in the pharmaceutical dosage form in a unit dose suitable for oral administration of siphonimod up to about 2 mg/day in total;

• fonesimod, or a pharmaceutically acceptable salt thereof, if present, is included in the pharmaceutical dosage form in a unit dose suitable for oral administration of fonesimod up to about 20 mg/day in total; and

• ozanimod, or a pharmaceutically acceptable salt thereof, if present, is included in said pharmaceutical dosage form in a unit dose suitable for oral administration of ozanimod up to about 1 mg/day in total;

• senerimod, or a pharmaceutically acceptable salt thereof, if present, is included in said pharmaceutical dosage form in a unit dose suitable for oral administration of senerimod up to about 4 mg/day in total;

• etracimod, or a pharmaceutically acceptable salt thereof, if present, is included in said pharmaceutical dosage form in a unit dose suitable for oral administration of etracimod up to about 2 mg/day in total; and

Amicelimod, or a pharmaceutically acceptable salt thereof, if present, is included in the pharmaceutical dosage form in a unit dose suitable for oral administration of amicelimod up to about 0.4 mg/day in total.

Said dosage form is particularly intended for once-daily (qd) administration of said unit dose.

13) A further embodiment relates to the pharmaceutical composition according to any one of embodiments 1) to 11), wherein the S1P1 receptor modulator, or a pharmaceutically acceptable salt thereof, is an oral compound of the S1P1 receptor modulator. included in a pharmaceutical dosage form suitable for administration,

fingolimod, or a pharmaceutically acceptable salt thereof, if present, is included in said pharmaceutical dosage form in a unit dose suitable for oral administration of fingolimod up to about 0.5 mg/day in total;

• siphonimod, or a pharmaceutically acceptable salt thereof, if present, is included in the pharmaceutical dosage form in a unit dose suitable for oral administration of siphonimod up to about 2 mg/day in total;

• fonesimod, or a pharmaceutically acceptable salt thereof, if present, is included in said pharmaceutical dosage form in a unit dose suitable for oral administration of fonesimod up to about 10 mg/day in total; and

• ozanimod, or a pharmaceutically acceptable salt thereof, if present, is included in said pharmaceutical dosage form in a unit dose suitable for oral administration of ozanimod up to about 0.5 mg/day in total;

- Senerimod, or a pharmaceutically acceptable salt thereof, if present, is included in said pharmaceutical dosage form in a unit dose suitable for oral administration of senerimod up to about 2 mg/day in total;

• etracimod, or a pharmaceutically acceptable salt thereof, if present, is included in said pharmaceutical dosage form in a unit dose suitable for oral administration of etracimod up to about 1 mg/day in total; and

Amicellimod, or a pharmaceutically acceptable salt thereof, if present, is included in the pharmaceutical dosage form in a unit dose suitable for oral administration of amicelimod up to about 0.2 mg/day in total.

Said dosage form is particularly intended for once-daily (qd) administration of said unit dose.

14) A further embodiment relates to the pharmaceutical composition according to any one of embodiments 1) to 13), wherein said S1P1 receptor modulator, or a pharmaceutically acceptable salt thereof, is provided as a monotherapy. An acceptable effective dose of the S1P1 receptor modulator or included as a dose of the S1P1 receptor modulator that is less than an acceptable effective dose (e.g., approval for such S1P1 receptor modulator for a particular disease or disorder when given as monotherapy) as specified in).

15) A further embodiment relates to the pharmaceutical composition according to any one of embodiments 1) to 13), wherein said S1P1 receptor modulator, or a pharmaceutically acceptable salt thereof, when provided as monotherapy, a dose of the S1P1 receptor modulator that is less than the acceptable effective dose of the S1P1 receptor modulator (eg as specified in the approval for such S1P1 receptor modulator for a particular disease or disorder when given as monotherapy) .

Such a combination pharmaceutical composition according to embodiments 1) to 15) is used for the prevention/prevention or treatment of diseases and disorders in which CXCR7 expression or its ligand and S1P both play a role and such a combination pharmaceutical composition at a pharmaceutically effective dose It is particularly useful in a method of preventing/preventing or treating diseases and disorders in which CXCR7 expression or its ligand and S1P both play a role, comprising administering to a subject in need thereof.

Diseases and disorders in which CXCR7 expression or both its ligand and S1P play a role are inter alia (i) in the inflammatory immune responses (such as migration, adhesion, survival, differentiation, polarization of cells) that occur in a variety of autoimmune and inflammatory disorders, and and/or (ii) diseases and disorders in which CXCR7 expression or its ligand and S1P both play a role in neurodegenerative processes (eg, glial cell activation, proliferation, migration, neuron survival, myelination).

In particular, diseases and disorders in which CXCR7 expression or its ligands play a role include, inter alia, diseases and disorders responsive to activation of CXCL12 receptor and/or CXCL11 receptor; as well as diseases and disorders that respond to opioid receptor signaling.

Those diseases and disorders in which CXCR7 expression or its ligands play a role are defined to include in particular:

• cancers such as malignant gliomas, brain tumors including glioblastoma multiforme; neuroblastoma; pancreatic cancer, including pancreatic adenocarcinoma/pancreatic adenocarcinoma; gastrointestinal cancers including colon carcinoma, hepatocellular carcinoma and gastric cancer; Kaposi's sarcoma; leukemia, including adult T-cell leukemia; lymphoma; lung cancer; breast cancer; rhabdomyosarcoma; prostate cancer; esophageal squamous cell carcinoma; oral squamous cell carcinoma; endometrial cancer; thyroid carcinoma, including papillary thyroid carcinoma; metastatic cancer; lung metastases; skin cancer, including melanoma and metastatic melanoma; bladder cancer; multiple myeloma; osteosarcoma; head and neck cancer; and renal carcinoma, including renal clear cell carcinoma, and metastatic renal clear cell carcinoma;

• Autoimmune and/or inflammatory diseases and disorders, including in particular

> Autoimmune and/or inflammatory demyelination diseases and disorders, including in particular

■ Multiple Sclerosis (MS); idiopathic (inflammatory) demyelination disease; and autoimmune encephalomyelitis (including acute disseminated encephalomyelitis (ADEM) and multiphase disseminated encephalomyelitis (MDEM));

■ Guillain-Barré syndrome; and chronic inflammatory demyelinizing polyneuropathy (CIDP); and

■ Other autoimmune and/or inflammatory demyelination diseases and disorders, which may be associated with the autoimmune and/or inflammatory demyelination diseases and disorders listed above, especially

• optic neuromyelitis spectrum disorders (including optic neuromyelitis (Debick's disease), and (acute) optic neuritis);

myelitis (including in particular transverse myelitis spectrum disorders such as in particular (acute) transverse myelitis, as well as acute flaccid myelitis, gray myelitis, leukomyelitis, and meningococcal myelitis);

• brainstem encephalitis; and

• anti-myelin oligodendrocyte glycoprotein (anti-MOG) associated diseases (including anti-MOG encephalomyelitis);

> rheumatoid arthritis (RA);

> inflammatory bowel disease (including IBD, particularly Crohn's disease and ulcerative colitis);

> systemic lupus erythematosus (SLE) (including neuropsychiatric systemic lupus erythematosus and lupus nephritis);

> interstitial cystitis; celiac disease; osteoarthritis; type I diabetes; psoriasis; autoimmune thyroiditis; Sjogren's syndrome; and vitiligo;

> chronic rhinosinusitis, asthma, chronic obstructive pulmonary disorder, atherosclerosis, myocarditis, acute lung injury, endometriosis, diabetic retinopathy and sarcoidosis;

> psoriatic arthritis; antiphospholipid syndrome; thyroiditis such as Hashimoto's thyroiditis; lymphocytic thyroiditis; myasthenia gravis; extrascleralitis; scleritis; Kawasaki disease; uveal-retinitis; uveitis, including posterior uveitis and uveitis associated with Behcet's disease; uveitis syndrome; allergic encephalomyelitis; atopic diseases such as rhinitis, conjunctivitis, dermatitis; and postinfectious autoimmune diseases including rheumatic fever and postinfectious glomerulonephritis;

> Rasmussen's encephalitis and musk syndrome (retinal cochlear cerebral vasculopathy);

> Ankylosing Spondylitis,

> Juvenile idiopathic arthritis, systemic sclerosis (systemic scleroderma), giant-cell arteritis (GCA or temporal arteritis), primary biliary cholangitis (PBC or primary biliary sclerosis); and

> Cytokine release syndrome followed by a strong viral infection including COVID-19 or acute respiratory distress syndrome;

• transplant rejection, including, inter alia, renal allograft rejection, cardiac allograft rejection, and graft-versus-host disease caused by hematopoietic stem cell transplantation;

• especially liver fibrosis, liver cirrhosis, pulmonary fibrosis, cardiac fibrosis; fibrosis, particularly idiopathic pulmonary fibrosis;

• ischemic injury, particularly including renal ischemia or cerebral ischemia;

• alopecia areata, eosinophilic esophagitis, dermatomyositis/polymyositis, atopic dermatitis, and pyogenic dermatosis gangrene;

• neurodegenerative disorders including, inter alia, amyotrophic lateral sclerosis (ALS) and Huntington's disease; as well as Alzheimer's disease (AD), Parkinson's disease (PD), and adrenal leukodystrophy; and

• diseases and disorders associated with opioid receptor signaling, particularly including neuropathic pain; as well as addiction disorders, mood disorders, and anxiety disorders.

It is understood that diseases and disorders in which CXCR7 expression or its ligands play a role include autoimmune and/or inflammatory demyelinating diseases and disorders, including in particular all forms of autoimmune neuritis.

It is also understood that neuropathic pain may be associated with any other disease or disorder in which CXCR7 expression or its ligand plays a role.

In a further aspect of the present invention, COMPOUND or a pharmaceutically acceptable salt thereof, when administered as a single active ingredient, is as defined hereinabove in "diseases and disorders in which CXCR7 expression or its ligand plays a role" It has now been found that it can be used for the prevention/prevention and treatment of COMPOUND can be used alone (ie as a single active ingredient), especially in such preferred particular dosage regimens, for the prophylaxis/prevention and treatment of said diseases and disorders; or COMPOUND, in combination with S1P1 receptor modulators, in particular in such preferred particular dosing regimens [eg in a fixed dose combination according to any one of embodiments 1) to 15); or in an equivalent non-fixed dose combination], and when used in combination, the "diseases and disorders in which CXCR7 expression or its ligand plays a role" means that CXCR7 expression or its ligand and S1P both play a role. diseases and disorders (diseases and disorders as defined herein).

Such a particular dosing regimen may comprise administering COMPOUND, or a pharmaceutically acceptable salt thereof, at a total dose of about 20 mg to about 300 mg/day, wherein the total dose is in particular in one unit dose ( given/administered once daily = once daily = qd), or as two separate unit doses (twice daily = twice daily = bid). For example, the total dose may be achieved by administering from about 20 mg qd to about 300 mg qd, or from about 10 mg bid to about 150 mg bid.

In particular, such dosing regimens include about 20 mg to 300 mg/day, about 20 mg to 200 mg/day, about 30 mg to 150 mg/day, about 40 mg to 150 mg/day, about 50 mg to 200 mg of COMPOUND. , from about 50 mg to 100 mg, from about 100 mg to 200 mg, or in particular from about 75 mg to 150 mg/day; Said total dose is given/administered in particular as one unit dose (qd), or as two separate unit doses (bid). Examples of such dosing regimens include administering COMPOUND at a total dose of about 200 mg, about 150 mg, about 100 mg, about 75 mg, about 50 mg, about 30 mg, or about 25 mg/day, wherein the total The dose is given as one unit dose (qd), or as two separate unit doses (bid), specific examples of such twice daily dosing regimens include, for example, about 100 mg bid, about 75 mg bid, about 50 mg bid, about 25 mg bid, or about 15 mg bid of COMPOUND.

For the avoidance of doubt, in the present invention any amount/unit dose in mg of COMPOUND refers to an amount/unit dose suitable for administration of COMPOUND in the free base form having a molecular weight of 522.56 g/mol in such amount/unit dose do. COMPOUND in a form different from the anhydrous free base in this pharmaceutical composition, such as a pharmaceutically acceptable salt; and/or in the form of a solvate such as a hydrate, such amount/unit dose in the pharmaceutical composition may need to be adjusted. It is understood that where the active ingredient is administered, for example in the form of a pharmaceutically acceptable salt, the amount of the active pharmaceutical ingredient in the pharmaceutical composition (eg said pharmaceutically acceptable salt) will be adjusted accordingly.

A particular dosage form/dosage regimen will generally have a maximum concentration C _max of the active ingredient in plasma of 80% to 125% of that value, and an area under the curve (AUC) of 80% to 125%, which it will achieve with a given dosage form and dosing regimen. ) is considered equivalent (bioequivalent according to FDA guidelines) when the exposure of the active ingredient expressed as

i) One particular aspect of the present invention is thus a COMPOUND for use in the prophylaxis/prevention or treatment of "diseases and disorders in which CXCR7 expression or its ligand plays a role" (as defined herein), or a COMPOUND thereof, It relates to a pharmaceutically acceptable salt, wherein COMPOUND is administered at a total dose of COMPOUND of from about 20 mg to about 300 mg (in particular from about 20 mg to about 200 mg; in particular from about 50 mg to about 150 mg)/day. (will be administered). In a subembodiment, the total dose is in particular as one unit dose per day [qd; for example from about 20 mg qd to about 300 mg qd (in particular from about 20 mg qd to about 200 mg qd; in particular from about 50 mg qd to about 150 mg qd)], or in two separate unit doses per day [bid; for example from about 10 mg bid to about 150 mg bid (especially from about 10 mg bid to about 100 mg bid; especially from about 25 mg bid to about 75 mg bid)] is provided/administered.

i) (a) in sub-embodiment, such diseases and disorders in which CXCR7 expression or its ligand plays a role include in particular:

• autoimmune and/or inflammatory diseases and disorders as defined herein; wherein the disease or disorder is in particular

> Autoimmune and/or inflammatory demyelinating diseases or disorders, including, inter alia, multiple sclerosis (MS), idiopathic inflammatory demyelinating disease, optic neuromyelitis spectrum disorders (including optic neuromyelitis and (acute) optic neuritis) , autoimmune encephalomyelitis (including acute disseminated encephalomyelitis (ADEM) and disseminated disseminated encephalomyelitis (MDEM)), myelitis (particularly transverse myelitis spectrum disorders such as in particular (acute) transverse myelitis, as well as acute flaccid myelitis, gray myelitis, leukomyelitis, and meningococcal myelitis), brainstem encephalitis, anti-myelin oligodendrocyte glycoprotein (anti-MOG) associated diseases (including anti-MOG encephalomyelitis); Guillain-Barré syndrome, chronic inflammatory demyelinating polyneuropathy (CIDP), and anti-myelin-associated glycoprotein (anti-MAG) peripheral neuropathy;

> rheumatoid arthritis (RA);

> inflammatory bowel disease (IBD); especially Crohn's disease or ulcerative colitis;

> systemic lupus erythematosus (SLE), including neuropsychiatric systemic lupus erythematosus and lupus nephritis;

> interstitial cystitis;

> celiac disease;

> osteoarthritis;

> psoriasis;

> Type I diabetes;

> Ankylosing spondylitis; or

> Cytokine release syndrome followed by a strong viral infection including COVID-19 or acute respiratory distress syndrome;

• transplant rejection, including, inter alia, renal allograft rejection, cardiac allograft rejection, and graft-versus-host disease caused by hematopoietic stem cell transplantation; or

• particularly amyotrophic lateral sclerosis (ALS) and Huntington's disease; as well as neurodegenerative disorders including Alzheimer's disease (AD), Parkinson's disease (PD), and adrenal leukodystrophy.

i) (b) in another subembodiment, such diseases and disorders in which CXCR7 expression or a ligand thereof play a role include, inter alia, liver fibrosis, liver cirrhosis, pulmonary fibrosis, cardiac fibrosis; in particular fibrosis, including idiopathic pulmonary fibrosis.

i) (c) in another subembodiment, such diseases and disorders in which CXCR7 expression or a ligand thereof plays a role include ischemic injury, particularly including renal ischemia or cerebral ischemia.

i) (d) in another subembodiment, such diseases and disorders in which CXCR7 expression or its ligands play a role include diseases or disorders associated with opioid receptor signaling, particularly including neuropathic pain; as well as addiction disorders, mood disorders, and anxiety disorders.

i) (e) in another subembodiment, such diseases and disorders in which CXCR7 expression or a ligand thereof play a role include in particular cancers such as brain tumors, including glioma malignancies, glioblastoma multiforme; neuroblastoma; pancreatic cancer, including pancreatic adenocarcinoma/pancreatic adenocarcinoma; gastrointestinal cancers including colon carcinoma, hepatocellular carcinoma and gastric cancer; Kaposi's sarcoma; leukemia, including adult T-cell leukemia; lymphoma; lung cancer; breast cancer; rhabdomyosarcoma; prostate cancer; esophageal squamous cell carcinoma; oral squamous cell carcinoma; endometrial cancer; thyroid carcinoma, including papillary thyroid carcinoma; metastatic cancer; lung metastases; skin cancer, including melanoma and metastatic melanoma; bladder cancer; multiple myeloma; osteosarcoma; head and neck cancer; and renal carcinoma, including renal clear cell carcinoma, metastatic renal clear cell carcinoma.

ii) A second particular aspect of the present invention relates to COMPOUND, or a pharmaceutically acceptable salt thereof, for use according to embodiment i) (or any of its sub-embodiments), wherein COMPOUND is about 20 mg to 200 mg/day of COMPOUND; in particular about 30 mg to 150 mg/day, about 40 mg to 150 mg/day, about 50 mg to 200 mg, about 50 mg to 150 mg, about 50 mg to 100 mg, or about 100 mg to 200 mg/day COMPOUND; In particular, a total dose of COMPOUND of about 75 mg to 150 mg/day is administered (which will be administered). In a subembodiment, the total dose is given/administered, particularly as one unit dose per day (qd), or as two separate unit doses per day (bid).

iii) A third particular aspect of the present invention relates to COMPOUND, or a pharmaceutically acceptable salt thereof, for use according to embodiment i) (or any of its sub-embodiments), wherein COMPOUND is about 200 mg COMPOUND of about 150 mg, about 100 mg, about 75 mg, about 50 mg, or about 30 mg/day; In particular, a total dose of COMPOUND of about 150 mg, about 100 mg, or about 75 mg/day is administered (which will be administered). In a subembodiment, the total dose is given/administered, particularly as one unit dose per day (qd), or as two separate unit doses per day (bid).

iv) a fourth particular aspect of the present invention relates to COMPOUND, or a pharmaceutically acceptable salt thereof, for use according to embodiment i) (or any of its sub-embodiments), wherein COMPOUND is about 200 mg COMPOUND of about 150 mg, about 125 mg, about 100 mg, about 75 mg, about 50 mg, about 30 mg, or about 25 mg/day; particularly at a total dose of COMPOUND of about 150 mg, about 125 mg, about 100 mg, or about 75 mg/day of COMPOUND; wherein the total dose is given/administered as one unit dose (qd) per day.

v) A fifth particular aspect of the present invention relates to COMPOUND, or a pharmaceutically acceptable salt thereof, for use according to embodiment i) (or any of its sub-embodiments), wherein COMPOUND is about 200 mg (given/administered as about 100 mg bid), about 150 mg (given/administered as about 75 mg bid), about 120 mg (given/administered as about 60 mg bid), about 100 mg (about 50 mg) given/administered bid), about 80 mg (about 40 mg given/administered bid), about 60 mg (given/administered about 30 mg bid), about 50 mg (about 25 mg given/administered bid) COMPOUND of about 30 mg (given/administered as about 15 mg bid)/day; in particular at a total dose of COMPOUND of about 150 mg (given/administered at about 75 mg bid), or about 100 mg (provided/administered at about 50 mg bid)/day (will be administered).

COMPOUND is according to the invention as a medicament as single active ingredient (optionally in combination with an S1P1 receptor modulator, ie not in combination with such a S1P1 receptor modulator, or in combination with such a S1P1 receptor modulator), for example In particular, it may be used in the form of a pharmaceutical composition for enteral administration or for parenteral administration.

vi) Another aspect of the present invention thus relates to a pharmaceutical composition comprising COMPOUND, or a pharmaceutically acceptable salt thereof, wherein COMPOUND is as defined in any one of embodiments i) to v). Included in a unit dose suitable for administering COMPOUND at the same total dose/day.

viii) A further aspect of the present invention relates to COMPOUND, or a pharmaceutically acceptable salt thereof, for use according to any one of embodiments i) to v), wherein COMPOUND is CXCR7 expression or a ligand thereof and S1P used for the prevention/prevention or treatment of diseases and disorders in which both play a role; Herein, only the necessary parts of the features of the following embodiments 16) to 35) are applied with slight modifications.

vii) Another aspect of the present invention provides, as an active ingredient, the COMPOUND according to any one of embodiments 1) to 15), or a pharmaceutically acceptable salt thereof, as an S1P1 receptor modulator, or a pharmaceutically acceptable salt thereof. In combination with a salt, it relates to a pharmaceutical composition comprising, wherein COMPOUND is comprised in a unit dose suitable for administration of COMPOUND at a total dose/day as defined in any one of embodiments i) to v); Such compositions are in particular for once-daily (qd) dosing/administration.

viii) A further aspect of the present invention relates to COMPOUND, or a pharmaceutically acceptable salt thereof, for use according to any one of embodiments i) to v), wherein COMPOUND is CXCR7 expression or a ligand thereof and S1P for use in the prevention/prevention or treatment of diseases and disorders in which both play a role; COMPOUND herein is intended to be used / administered / intended to be administered in combination with an S1P1 receptor modulator, or a pharmaceutically acceptable salt thereof; Here, only the necessary parts of the characteristics of any one of the following embodiments 16) to 48) are applied with slight modifications.

Diseases and disorders in which CXCR7 expression or its ligand and S1P both play a role are those in which CXCR7 expression or its ligand, preferably having a component of an inflammatory immune response, plays a role.

Such diseases and disorders in which CXCR7 expression or its ligand and S1P both play a role include, inter alia, autoimmune and/or inflammatory diseases and disorders, transplant rejection, and neurodegenerative diseases and disorders; It may be defined as including autoimmune diseases and disorders, particularly autoimmune and/or inflammatory demyelinating diseases and disorders, particularly having an inflammatory component.

The term “graft rejection” refers to rejection of transplanted organs such as kidney, liver, heart, lung, pancreas, cornea, and skin; graft versus host disease caused by hematopoietic stem cell transplantation; can be defined as including chronic allograft rejection and chronic allograft angiopathy.

The term “neurodegenerative diseases and disorders” refers to neurodegeneration in which both CXCR7 expression or its ligand and S1P play a role, particularly in the neurodegeneration associated with such diseases and disorders (eg glial cell activation, neuronal survival, myelination). can be defined as including diseases and disorders. Specific examples include amyotrophic lateral sclerosis (ALS), Alzheimer's disease (AD), Parkinson's disease (PD), Huntington's disease, and adrenal leukodystrophy.

The term “autoimmune and/or inflammatory diseases and disorders” refers to any autoimmune and/or inflammatory diseases or disorders, in particular autoimmune diseases and disorders having an inflammatory component, in particular in which CXCR7 expression or its ligand and S1P both play a role. refers to Examples of such autoimmune and/or inflammatory diseases and disorders include autoimmune and/or inflammatory demyelinating diseases and disorders, including all forms of autoimmune neuritis. In particular, autoimmune and/or inflammatory demyelinating diseases and disorders include multiple sclerosis (MS), Guillain-Barré syndrome, chronic inflammatory demyelinating polyneuropathy (CIDP), and other autoimmune and/or inflammatory demyelinizing diseases and disorders and Disorders (which may be associated with the autoimmune and/or inflammatory demyelination diseases and disorders listed above) such as optic neuromyelitis spectrum disorders (including optic neuromyelitis (Devic's disease), and (acute) optic neuritis), autologous immune encephalomyelitis (including acute disseminated encephalomyelitis (ADEM) and disseminated encephalomyelitis multiforme (MDEM)), myelitis (particularly transverse myelitis spectrum disorders such as in particular (acute) transverse myelitis, as well as acute flaccid myelitis, gray myelitis, leukomyelitis) , and meningococcal myelitis), brainstem encephalitis, and diseases associated with anti-myelin oligodendrocyte glycoprotein (anti-MOG) (including anti-MOG encephalomyelitis); rheumatoid arthritis (RA); inflammatory bowel disease (including IBD, particularly Crohn's disease and ulcerative colitis); systemic lupus erythematosus (SLE) (including neuropsychiatric systemic lupus erythematosus and lupus nephritis); interstitial cystitis; celiac disease; osteoarthritis; psoriasis; and type I diabetes. In addition, autoimmune and inflammatory diseases and disorders also include psoriatic arthritis; antiphospholipid syndrome; thyroiditis such as Hashimoto's thyroiditis; lymphocytic thyroiditis; myasthenia gravis; extrascleralitis; scleritis; Kawasaki disease; uveal-retinitis; uveitis, including posterior uveitis, and uveitis associated with Behcet's disease; uveitis syndrome; allergic encephalomyelitis; atopic diseases such as rhinitis, conjunctivitis, dermatitis; and disorders such as postinfectious autoimmune diseases including rheumatic fever and postinfectious glomerulonephritis.

In addition to those listed above, additional autoimmune and/or inflammatory diseases or disorders in which CXCR7 expression or its ligand and S1P both play a role include autoimmune and/or inflammatory demyelinating diseases and disorders such as Rasmussen's encephalitis and musculoskeletal syndrome. (retina cochlear cerebral angiopathy); as well as other autoimmune and inflammatory diseases and disorders such as ankylosing spondylitis, juvenile idiopathic arthritis, systemic sclerosis (systemic scleroderma), giant-cell arteritis (GCA or temporal arteritis), primary biliary cholangitis (PBC or primary biliary sclerosis); and cytokine release syndrome followed by strong viral infections including COVID-19 or acute respiratory distress syndrome.

Specific examples of autoimmune and/or inflammatory diseases and disorders are

Autoimmune and/or inflammatory demyelination, including, inter alia, multiple sclerosis (MS), Guillain-Barré syndrome, chronic inflammatory demyelinating polyneuropathy (CIDP), and other autoimmune and/or inflammatory demyelination diseases and disorders diseases and disorders;

• rheumatoid arthritis (RA);

• inflammatory bowel disease (IBD), particularly including Crohn's disease and ulcerative colitis;

• systemic lupus erythematosus (SLE) (including neuropsychiatric systemic lupus erythematosus and lupus nephritis); and, in addition to those listed above,

ㆍ Ankylosing spondylitis, and

ㆍ Cytokine release syndrome followed by a strong viral infection including COVID-19 or acute respiratory distress syndrome.

In the first sub-embodiment, the term “autoimmune and/or inflammatory diseases and disorders” refers in particular to multiple sclerosis (MS), Guillain-Barré syndrome, chronic inflammatory demyelinating polyneuropathy (CIDP), and other as defined herein. autoimmune and/or inflammatory demyelinating diseases and disorders such as autoimmune and/or inflammatory demyelinating diseases and disorders, including in particular autoimmune encephalomyelitis and myelitis.

In a second sub-embodiment, the term “autoimmune and/or inflammatory diseases and disorders” refers to inflammatory bowel diseases, including in particular Crohn's disease and ulcerative colitis.

In a third sub-embodiment, the term “autoimmune and/or inflammatory diseases and disorders” refers to systemic lupus erythematosus (SLE), including neuropsychiatric systemic lupus erythematosus and lupus nephritis.

In a fourth sub-embodiment, the term “autoimmune and/or inflammatory diseases and disorders” refers to ankylosing spondylitis.

In the fifth sub-embodiment, the term “autoimmune and/or inflammatory diseases and disorders” refers to a cytokine release syndrome followed by a strong viral infection including COVID-19 or acute respiratory distress syndrome.

The term "autoimmune and/or inflammatory demyelination diseases and disorders" refers to demyelinated diseases and disorders of the central nervous system such as in particular multiple sclerosis (MS), as well as idiopathic inflammatory demyelinating diseases, optic neuromyelitis spectrum diseases (optic nerve myelitis (including Debick's disease) and (acute) optic neuritis), autoimmune encephalomyelitis (including acute disseminated encephalomyelitis (ADEM) and disseminated disseminated encephalomyelitis (MDEM)), myelitis (in particular transverse myelitis spectrum disorders such as in particular (acute) ) transverse myelitis, as well as acute flaccid myelitis, including gray myelitis, leukomyelitis, and meningococcal myelitis), brainstem encephalitis, and diseases associated with anti-myelin oligodendrocyte glycoprotein (anti-MOG) (anti-MOG encephalomyelitis) including); as well as autoimmune and/or inflammatory demyelination diseases and disorders of the peripheral nervous system such as in particular Guillain-Barré syndrome and its chronic relative chronic inflammatory demyelinating polyneuropathy (CIDP, also known as chronic relapsing polyneuropathy (CRP)) ), and anti-myelin-associated glycoprotein (anti-MAG) peripheral neuropathy.

In the first sub-embodiment, the term "autoimmune and/or inflammatory demyelinating diseases and disorders" is in particular multiple sclerosis (MS), Guillain-Barré syndrome, chronic inflammatory demyelinating polyneuropathy (CIDP), and as defined herein other autoimmune and/or inflammatory demyelination diseases and disorders such as in particular autoimmune encephalomyelitis and myelitis.

In a second sub-embodiment, the term “autoimmune and/or inflammatory demyelination diseases and disorders” refers in particular to a spectrum disorder of transverse myelitis such as myelitis which is in particular (acute) transverse myelitis;

The transverse myelitis spectrum disorder is

- is idiopathic (cause unknown), or

Caused by / associated with multiple sclerosis, or

Caused by/associated with SLE, optic neuromyelitis spectrum disorder, antiphospholipid syndrome, or other autoimmune and inflammatory diseases and disorders as defined herein; or

Infections caused by infectious diseases such as viruses, bacteria, fungi, or parasites

[especially bacterial infections (eg infections by Mycoplasma pneumoniae, Bartonella hensellae, Borrelia (Lyme disease), Campylobacter jejuni, Sophilis, tuberculosis (TB)); and

viral infections (including, for example, viral meningoencephalitis (meningitis), or infections with HIV, herpes simplex, herpes zoster, cytomegalovirus, Epstein-Barr virus, flaviviruses such as Zika virus and West Nile virus)] caused by / associated with; or

• Can be caused by / associated with vaccination (including vaccination against coronavirus such as SARS-CoV / SARS-CoV-1).

In a third sub-embodiment, the term "autoimmune and/or inflammatory demyelination diseases and disorders" refers in particular to optic neuromyelitis spectrum disorders such as in particular (acute) optic neuritis, wherein the optic neuromyelitis spectrum disorders are

- is idiopathic (cause unknown), or

Caused by / associated with multiple sclerosis, or

• caused by/associated with SLE, or other autoimmune and/or inflammatory diseases and disorders; or

ㆍ May be caused by / associated with infectious diseases including Lyme disease.

Likewise, in the fourth sub-embodiment, the term “autoimmune and/or inflammatory demyelination diseases and disorders” means in particular any autoimmune and/or inflammatory demyelination disease or disorder, such as in particular optic neuromyelitis spectrum disorders such as in particular ( Acute) refers to MS associated with optic neuritis.

The term “idiopathic inflammatory demyelinating disease” includes inflammatory demyelinating diseases of unknown etiology; It refers in particular to multiple sclerosis of a heterogeneous or borderline type that differs, for example, in terms of chronicity, severity, and clinical course.

A particular example of "autoimmune and/or inflammatory diseases and disorders" is the autoimmune demyelinating disease multiple sclerosis (MS), understood that MS can be further classified as relapsing-remitting MS, primary progressive MS or secondary progressive MS. do.

A particular feature of autoimmune and/or inflammatory demyelination diseases and disorders such as in particular MS relates to the demyelination aspects present in such diseases or disorders. Therefore, one aspect of the present invention relates to the treatment of an autoimmune and/or inflammatory demyelination disease or disorder such as in particular MS, wherein the rate of progression of the disease or disorder is reduced, in particular the rate of progression of demyelination and/or or a reduced rate of appearance of irreversible neurodegenerative damage such as axonal damage. A further aspect of the invention relates to the treatment of an autoimmune and/or inflammatory demyelination disease or disorder such as in particular MS, wherein said treatment has an effect on/results in remyelination.

The term “clinical solitary syndrome” (CIS) refers to the first episode of neurological symptoms lasting at least 24 h and caused by inflammation or demyelination in the central nervous system (CNS). Although this episode is usually characteristic of an autoimmune and/or inflammatory demyelination disease or disorder, in particular MS, patients diagnosed as having experienced CIS may subsequently develop an autoimmune and/or inflammatory demyelination disease or disorder, particularly They may or may not develop MS. When CIS is accompanied by lesions similar to those seen in MS confirmed using, for example, brain MRI (magnetic resonance imaging), the person is more likely to be diagnosed with a second episode of neurological symptoms and relapsing MS. When CIS is not accompanied by MS-like lesions on brain MRI, the person is much less likely to develop MS. Diagnostic criteria for MS (see, for example, the 2018 revised guidelines: https://www.mscare.org/page/MRI_protocol) provide evidence of earlier episodes of impairment in other locations and It makes it possible to diagnose MS in patients who have also experienced CIS with specific findings on brain MRI suggesting active inflammation in areas other than those areas. Individuals with CIS may be considered at high risk of developing MS. In the United States, such patients may be treated for that purpose by disease-modulating therapies approved by the United States Food and Drug Administration (FDA). Early treatment of CIS has been shown to delay the onset of autoimmune and/or inflammatory demyelination diseases or disorders, particularly MS.

The term prophylaxis/prevention of an autoimmune and/or inflammatory demyelination disease or disorder therefore includes in particular delaying the onset of such autoimmune and/or inflammatory demyelination disease or disorder [for example by preventing demyelination and/or by remyelination of demyelination that occurs early (eg in clinical solitary syndrome)].

Therefore, another aspect of the present invention relates to a pharmaceutical composition according to embodiments 1) to 15) for the prevention/prevention of autoimmune and/or inflammatory demyelination diseases or disorders, in particular MS, wherein the autoimmune and Prevention/prevention of an inflammatory demyelination disease or disorder, in particular MS, may prevent the development of said autoimmune and/or inflammatory demyelination disease or disorder, in particular MS, in a patient who has experienced CIS/diagnosed as having experienced CIS. including delay.

In a specific embodiment of the present invention, the combination pharmaceutical composition according to embodiments 1) to 15) prevents or treats demyelination; In particular the subject to be treated has been diagnosed as having an autoimmune and/or inflammatory demyelination disease and disorder as defined herein.

In a further specific embodiment of the present invention, the combination pharmaceutical composition according to embodiments 1) to 15) prevents or treats demyelination in a patient, wherein the prevention or treatment of demyelination additionally has a remyelination effect includes; In particular the subject to be treated has been diagnosed as having an autoimmune and/or inflammatory demyelination disease and disorder as defined herein.

16) 　 A second aspect of the present invention relates to the prevention/prevention or treatment of diseases and disorders in which CXCR7 expression or its ligand and S1P both play a role, in particular autoimmune and inflammatory diseases and disorders, transplant rejection, and neurodegenerative diseases and COMPOUND for use in the prophylaxis/prevention or treatment of disorders (especially autoimmune and/or inflammatory diseases and disorders; in particular autoimmune diseases and disorders having an inflammatory component, in particular autoimmune and/or inflammatory demyelinating diseases and disorders); or a pharmaceutically acceptable salt thereof; wherein COMPOUND is administered in combination with an S1P1 receptor modulator, or a pharmaceutically acceptable salt thereof (which is intended to be administered).

17) A further embodiment relates to COMPOUND for use according to embodiment 16), or a pharmaceutically acceptable salt thereof; Such use herein is for the treatment of

• autoimmune and/or inflammatory diseases and disorders; wherein said disease or disorder is in particular

> Autoimmune and/or inflammatory demyelinating diseases or disorders, including in particular multiple sclerosis (MS); idiopathic inflammatory demyelination disease; optic neuromyelitis spectrum disorders including optic neuromyelitis and (acute) optic neuritis; autoimmune encephalomyelitis, including acute disseminated encephalomyelitis (ADEM) and multiphase disseminated encephalomyelitis (MDEM); especially transverse myelitis spectrum disorders such as myelitis, including in particular (acute) transverse myelitis, as well as acute flaccid myelitis, gray myelitis, leukomyelitis, and meningococcal myelitis; brainstem encephalitis; anti-myelin oligodendrocyte glycoprotein (anti-MOG) associated diseases, including anti-MOG encephalomyelitis; Guillain-Barré Syndrome; chronic inflammatory demyelinizing polyneuropathy (CIDP); and anti-myelin-associated glycoprotein (anti-MAG) peripheral neuropathy;

> rheumatoid arthritis (RA);

> inflammatory bowel disease (IBD); especially Crohn's disease or ulcerative colitis;

> systemic lupus erythematosus (SLE), including neuropsychiatric systemic lupus erythematosus and lupus nephritis;

> interstitial cystitis;

> celiac disease;

> osteoarthritis;

> psoriasis;

> Type I diabetes; or, in addition to those listed above,

> Ankylosing spondylitis; or

> Cytokine release syndrome followed by a strong viral infection including COVID-19 or acute respiratory distress syndrome;

• transplant rejection; wherein said transplant rejection is in particular rejection of a transplanted organ such as kidney, liver, heart, lung, pancreas, cornea, or skin; graft versus host disease caused by hematopoietic stem cell transplantation; chronic allograft rejection and chronic allograft angiopathy; or

• neurodegenerative diseases and disorders; wherein said neurodegenerative diseases and disorders are in particular amyotrophic lateral sclerosis (ALS), or Huntington's disease; or further, Alzheimer's disease (AD), Parkinson's disease (PD), or adrenal leukodystrophy.

18) A further embodiment relates to COMPOUND, or a pharmaceutically acceptable salt thereof, for use according to embodiment 16), wherein CXCR7 expression or its ligand and S1P both play a role, said diseases and disorders is an autoimmune and/or inflammatory disease or disorder selected from:

• especially multiple sclerosis (MS); idiopathic inflammatory demyelination disease; autoimmune encephalomyelitis, including acute disseminated encephalomyelitis (ADEM) and multiphase disseminated encephalomyelitis (MDEM); Guillain-Barré Syndrome; chronic inflammatory demyelinizing polyneuropathy (CIDP); anti-myelin-associated glycoprotein (anti-MAG) peripheral neuropathy; and myelin oligodendrocyte glycoprotein (MOG)-antibody associated diseases; as well as autoimmune and/or inflammatory demyelination diseases, particularly selected from myelitis, including in particular transverse myelitis spectrum disorders such as in particular (acute) transverse myelitis, as well as myelitis including acute flaccid myelitis, gray myelitis, leukomyelitis, and meningococcal myelitis or disability;

• inflammatory bowel diseases, especially selected from Crohn's disease and ulcerative colitis; or

• Systemic lupus erythematosus (SLE), including neuropsychiatric systemic lupus erythematosus and lupus nephritis.

The term “prevention/prevention or treatment” in the context of the diseases and disorders as defined herein, in particular according to embodiments 16), 17) and 18), refers in particular to the treatment of said diseases and disorders; In the case of chronic progressive diseases and disorders (including primary or secondary progressive and relapsing forms), the term "treatment" refers in particular to a reduction in the rate of progression of said disease or disorder. Such reduction in the rate of progression may include, for example, a reduced rate of progression of the disorder; reduced rate of irreversible neurodegenerative damage such as axonal damage; reduced rate of demyelination; Alternatively, when the disease or disorder is related to the brain/central nervous system, it can be expressed by a reduced rate of brain atrophy/cerebral atrophy (eg as diagnosed in particular by magnetic resonance imaging (MRI)).

In another aspect the term "prevention/prevention or treatment" in the context of the diseases and disorders as defined herein, in particular according to embodiments 16), 17) and 18), in particular also means a risk or risk of developing such a disease or disorder. subjects diagnosed with lichen; Refers to the prevention/prevention of said diseases and disorders, in particular delaying the onset of said diseases or disorders, e.g. in a subject who has experienced/diagnosed as having experienced Clinical Solitary Syndrome (CIS), such CIS generally It is known to suggest that such subjects may be at risk. Such a delay in onset may be expressed, for example, by an increase in the time until a diagnosis of the disease or disorder can be established; especially increased time to disability; if applicable, increase in time to first relapse; (progressive) increased time to diagnosis of irreversible neurodegenerative injury such as axonal injury; increased time to diagnosis of demyelination; Alternatively, if the disease or disorder is related to the brain/central nervous system, it can be expressed by an increase in the time to diagnosis of progressive brain atrophy/cerebral atrophy (eg diagnosed in particular by magnetic resonance imaging (MRI)).

19) A further embodiment relates to COMPOUND, or a pharmaceutically acceptable salt thereof, for use in the prevention/prevention or treatment of a neurodegenerative disease or disorder; wherein said neurodegenerative disease or disorder is in particular amyotrophic lateral sclerosis (ALS) or Huntington's disease; or Alzheimer's disease (AD), Parkinson's disease (PD), or adrenal leukodystrophy; wherein COMPOUND is administered in combination with an S1P1 receptor modulator, or a pharmaceutically acceptable salt thereof (which is intended to be administered).

20) A further embodiment relates to COMPOUND, or a pharmaceutically acceptable salt thereof, for use according to embodiment 19), wherein such use is for the treatment of a patient diagnosed with said neurodegenerative disease or disorder, , the treatment reduces the rate of progression of the neurodegenerative disease or disorder.

21) A further embodiment relates to COMPOUND for use according to embodiment 20), or a pharmaceutically acceptable salt thereof; Such a reduced rate of progression of said neurodegenerative disease or disorder here can be expressed by a reduced rate of brain atrophy/cerebral atrophy (such as diagnosed in particular by magnetic resonance imaging (MRI)).

22) A further embodiment relates to COMPOUND, or a pharmaceutically acceptable salt thereof, for use according to any one of embodiments 16) to 18), wherein COMPOUND is an autoimmune and/or inflammatory demyelination disease or for use in the prevention/prevention or treatment of a disorder;

In particular such autoimmune and/or inflammatory demyelinating diseases or disorders are

• Multiple Sclerosis (MS);

ㆍ Idiopathic inflammatory demyelination disease;

• optic neuromyelitis spectrum disorders (including optic neuromyelitis and (acute) optic neuritis);

• autoimmune encephalomyelitis (including acute disseminated encephalomyelitis (ADEM) and disseminated encephalomyelitis multiforme (MDEM));

myelitis (including in particular transverse myelitis spectrum disorders such as in particular (acute) transverse myelitis, as well as acute flaccid myelitis, gray myelitis, leukomyelitis, and meningococcal myelitis);

• brainstem encephalitis;

• anti-myelin oligodendrocyte glycoprotein (anti-MOG) associated diseases (including anti-MOG encephalomyelitis);

• Guillain-Barré syndrome;

• Chronic inflammatory demyelinizing polyneuropathy (CIDP); or

• Anti-myelin-associated glycoprotein (anti-MAG) peripheral neuropathy.

23) A further embodiment relates to COMPOUND, or a pharmaceutically acceptable salt thereof, for use according to embodiment 22), wherein such use is used in a diagnosis of an autoimmune and/or inflammatory demyelination disease or disorder. for the treatment of a patient, wherein said treatment reduces the rate of progression of said autoimmune and/or inflammatory demyelination disease or disorder; In particular such autoimmune and/or inflammatory demyelinating diseases or disorders are as listed in embodiment 22).

24) A further embodiment relates to COMPOUND, or a pharmaceutically acceptable salt thereof, for use according to embodiment 22), wherein such use is for the prevention of said autoimmune and/or inflammatory demyelination disease or disorder. /is for prevention; the onset of said autoimmune and/or inflammatory demyelination disease or disorder is delayed in a subject at risk/diagnosed at risk of developing such disease or disorder; In particular such autoimmune and/or inflammatory demyelinating diseases or disorders are as listed in embodiment 22).

25) A further embodiment relates to COMPOUND for use according to embodiment 23), or a pharmaceutically acceptable salt thereof; wherein such reduced rate of progression of said autoimmune and/or inflammatory demyelination disease or disorder may be expressed by a reduced rate of demyelination and/or reduced rate of irreversible neurodegenerative damage such as axonal damage. .

26) A further embodiment relates to COMPOUND for use according to embodiments 23) or 25), or a pharmaceutically acceptable salt thereof; Here such a reduced rate of progression of said autoimmune and/or inflammatory demyelination disease or disorder may be expressed in particular by a reduced rate of progression of the disorder.

27) A further embodiment relates to COMPOUND for use according to embodiments 23), 25) or 26), or a pharmaceutically acceptable salt thereof; wherein such a reduced rate of progression of said autoimmune and/or inflammatory demyelination disease or disorder can be expressed by a reduced rate of brain atrophy/cerebral atrophy (such as diagnosed in particular by magnetic resonance imaging (MRI)) there is; It is understood that said autoimmune and/or inflammatory demyelinating disease or disorder is in particular MS, in particular relapsing-remitting multiple sclerosis (RRMS), secondary progressive multiple sclerosis (SPMS), or primary progressive multiple sclerosis (PPMS).

28) A further embodiment relates to COMPOUND, or a pharmaceutically acceptable salt thereof, for use according to embodiment 24), wherein said delay of onset of said autoimmune and/or inflammatory demyelination disease or disorder is expressed by

• by increasing the time until a diagnosis of said disease or disorder can be established;

• by an increase in time to disability;

by an increase in time to first relapse, if said disease or disorder is characterized by disease progression including relapse;

• (progressive) (irreversible) by increased time to diagnosis of neurodegenerative damage such as axonal damage;

• by increased time to diagnosis of demyelination; or

By increasing the time to diagnosis of progressive brain atrophy/cerebral atrophy (eg diagnosed in particular by magnetic resonance imaging (MRI)), if the disease or disorder is related to the brain/central nervous system.

29) A further embodiment relates to COMPOUND, or a pharmaceutically acceptable salt thereof, for use according to any one of embodiments 22) to 28), wherein said prophylaxis/prevention or treatment comprises the effect of remyelination induce

The effect of remyelination can be expressed, for example, as tissue repair (eg of the extracellular matrix). The effect of such remyelination is well known magnetic resonance imaging (MRI), including for example magnetization transfer imaging (MTI), and in particular diffusion weighted magnetic resonance imaging (DWI or DW-MRI), in particular diffusion tensor imaging (DTI). can be visualized by technology.

30) A further embodiment relates to COMPOUND, or a pharmaceutically acceptable salt thereof, for use according to embodiment 22), wherein such use is for the treatment of a patient diagnosed with MS; In particular said treatment reduces the rate of progression of MS, which may be expressed in particular by a reduced rate of demyelination and/or a reduced rate of irreversible neurodegenerative damage such as axonal damage; It is understood that such MS may in particular be relapsing-remitting multiple sclerosis (RRMS), secondary progressive multiple sclerosis (SPMS), or primary progressive multiple sclerosis (PPMS).

31) A further embodiment relates to COMPOUND, or a pharmaceutically acceptable salt thereof, for use according to embodiment 22), wherein such use is for the treatment of a patient diagnosed with MS; In particular said treatment reduces the rate of progression of MS, and such reduced rate of progression of MS can be expressed in particular by a reduced rate of progression of the disorder; It is understood that such MS may in particular be relapsing-remitting multiple sclerosis (RRMS), secondary progressive multiple sclerosis (SPMS), or primary progressive multiple sclerosis (PPMS).

32) A further embodiment relates to COMPOUND, or a pharmaceutically acceptable salt thereof, for use according to embodiment 22), wherein such use is for the treatment of a patient diagnosed with MS; In particular said treatment reduces the rate of progression of MS, which can be expressed in particular by a reduced rate of brain atrophy/cerebral atrophy (such as diagnosed in particular by magnetic resonance imaging (MRI)) and ; It is understood that such MS may in particular be relapsing-remitting multiple sclerosis (RRMS), secondary progressive multiple sclerosis (SPMS), or primary progressive multiple sclerosis (PPMS).

33) A further embodiment relates to COMPOUND, or a pharmaceutically acceptable salt thereof, for use according to embodiment 22), wherein such use is for the treatment of a patient diagnosed with MS; wherein the treatment ameliorates the symptoms of MS, and such amelioration of the symptoms of MS can be expressed in particular by the effect of remyelination; It is understood that such MS may in particular be relapsing-remitting multiple sclerosis (RRMS), secondary progressive multiple sclerosis (SPMS), or primary progressive multiple sclerosis (PPMS).

34) A further embodiment relates to COMPOUND, or a pharmaceutically acceptable salt thereof, for use according to embodiment 22), wherein such use is for the prophylaxis/prevention of MS, wherein said prophylaxis of MS /preventing includes delaying the onset of MS in a patient who has/has been diagnosed with CIS; It is understood that such MS may in particular be relapsing-remitting multiple sclerosis (RRMS).

35) A further embodiment relates to COMPOUND, or a pharmaceutically acceptable salt thereof, for use according to any one of embodiments 30) to 34), wherein said prophylaxis/prevention or treatment comprises the effect of remyelination induce

36) A further embodiment relates to COMPOUND, or a pharmaceutically acceptable salt thereof, for use according to any one of embodiments 16) to 35), wherein the S1P1 receptor modulator, or a pharmaceutically acceptable salt thereof The salt is fingolimod, ponesimod, siphonimod, ozanimod, senerimod, etrasimod, amicelimod, seralifimod, GSK 2018682, or CS-0777; or, furthermore, mokrabimod (in particular fingolimod, ponesimod, siphonimod, or ozanimod; or, furthermore, senerimod); or a pharmaceutically acceptable salt thereof.

37) A further embodiment relates to COMPOUND, or a pharmaceutically acceptable salt thereof, for use according to any one of embodiments 16) to 35), wherein the S1P1 receptor modulator, or a pharmaceutically acceptable salt thereof The salt is selected from fingolimod, fonesimod, siphonimod, ozanimod, senerimod, etrasimod, (especially fingolimod, fonesimod, siphonimod, or ozanimod; or, further, senerimod), or a pharmaceutically acceptable salt thereof.

In a subembodiment, such combination use (particularly use in combination with fingolimod, fonesimod, siphonimod, or ozanimod) is an autoimmune and/or inflammatory demyelination disease or disorder (particularly multiple sclerosis (MS) ( inflammatory bowel disease including colitis; or for the prevention or treatment of systemic lupus erythematosus (SLE).

38) A further embodiment relates to COMPOUND, or a pharmaceutically acceptable salt thereof, for use according to any one of embodiments 16) to 35), wherein the S1P1 receptor modulator, or a pharmaceutically acceptable salt thereof The salt is senerimod, ozanimod, etrasimod, or amicelimod (especially senerimod or etracimod), or a pharmaceutically acceptable salt thereof.

In a subembodiment, such combined use is for the prophylaxis or treatment of an inflammatory bowel disease particularly selected from Crohn's disease and ulcerative colitis; or for the prevention or treatment of systemic lupus erythematosus (SLE).

39) A further embodiment relates to COMPOUND, or a pharmaceutically acceptable salt thereof, for use according to any one of embodiments 16) to 35), wherein the S1P1 receptor modulator, or a pharmaceutically acceptable salt thereof The salt is fingolimod, or a pharmaceutically acceptable salt thereof.

40) A further embodiment relates to COMPOUND, or a pharmaceutically acceptable salt thereof, for use according to any one of embodiments 16) to 35), wherein the S1P1 receptor modulator, or a pharmaceutically acceptable salt thereof The salt is fonesimod, or a pharmaceutically acceptable salt thereof.

41) A further embodiment relates to COMPOUND, or a pharmaceutically acceptable salt thereof, for use according to any one of embodiments 16) to 35), wherein the S1P1 receptor modulator, or a pharmaceutically acceptable salt thereof The salt is siphonimod, or a pharmaceutically acceptable salt thereof.

42) A further embodiment relates to COMPOUND, or a pharmaceutically acceptable salt thereof, for use according to any one of embodiments 16) to 35), wherein the S1P1 receptor modulator, or a pharmaceutically acceptable salt thereof The salt is ozanimod, or a pharmaceutically acceptable salt thereof.

43) A further embodiment relates to COMPOUND, or a pharmaceutically acceptable salt thereof, for use according to any one of embodiments 16) to 35), wherein the S1P1 receptor modulator, or a pharmaceutically acceptable salt thereof The salt is senerimod, or a pharmaceutically acceptable salt thereof.

In a sub-embodiment, such combination use is particularly for the prophylaxis/prevention or treatment of an autoimmune and/or inflammatory demyelination disease or disorder according to any one of embodiments 22) to 29); In particular for the prevention/prevention or treatment of MS according to any one of embodiments 30) to 35).

In another subembodiment, such combination use is particularly for the prevention/prevention or treatment of systemic lupus erythematosus (SLE).

44) A further embodiment relates to COMPOUND, or a pharmaceutically acceptable salt thereof, for use according to any one of embodiments 16) to 35), wherein the S1P1 receptor modulator, or a pharmaceutically acceptable salt thereof The salt is etracimod, or a pharmaceutically acceptable salt thereof.

45) a further embodiment relates to COMPOUND for use according to any one of embodiments 16) to 44), or a pharmaceutically acceptable salt thereof; wherein the S1P1 receptor modulator, or a pharmaceutically acceptable salt thereof, will be administered in a pharmaceutical dosage form suitable for oral administration of the S1P1 receptor modulator, wherein

Fingolimod, or a pharmaceutically acceptable salt thereof, if present, will be administered in unit doses suitable for oral administration of fingolimod up to about 0.5 mg/day in total in said pharmaceutical dosage form;

siphonimod, or a pharmaceutically acceptable salt thereof, if present, will be administered in unit doses suitable for oral administration of siphonimod up to about 2 mg/day in total in said pharmaceutical dosage form;

- fonesimod, or a pharmaceutically acceptable salt thereof, when present, in total in said pharmaceutical dosage form up to about 20 mg/day (in particular about 10-20 mg/day, especially 20 mg/day, or 10 mg/day) in a unit dose suitable for oral administration of fonesimod; and

- Ozanimod, or a pharmaceutically acceptable salt thereof, when present, in total in said pharmaceutical dosage form up to about 1 mg/day (in particular about 0.5-1 mg/day, in particular 1 mg/day, or 0.5 mg/day) in unit doses suitable for oral administration of ozanimod;

- Senerimod, or a pharmaceutically acceptable salt thereof, if present, in total in said pharmaceutical dosage form up to about 4 mg/day (in particular about 2-4 mg/day, in particular 4 mg/day, or 2 mg/day) will be administered in unit doses suitable for oral administration of senerimod;

Etracimod, or a pharmaceutically acceptable salt thereof, when present, in total in said pharmaceutical dosage form, up to about 2 mg/day (in particular about 1-2 mg/day, in particular 2 mg/day, or 1 mg/day) will be administered in unit doses suitable for oral administration of etracemod;

- Amicellimod, or a pharmaceutically acceptable salt thereof, if present, in total in said pharmaceutical dosage form up to about 0.4 mg/day (in particular about 0.2-0.4 mg/day, in particular 0.4 mg/day, or 0.2 mg/day) in a unit dose suitable for oral administration of amicelimod.

Said dosage form is particularly intended for once-daily (qd) administration of said unit dose.

46) A further embodiment relates to COMPOUND for use according to any one of embodiments 16) to 45), or a pharmaceutically acceptable salt thereof; wherein the S1P1 receptor modulator, or a pharmaceutically acceptable salt thereof, will be administered in a pharmaceutical dosage form suitable for oral administration of the S1P1 receptor modulator, wherein

Fingolimod, or a pharmaceutically acceptable salt thereof, if present, will be administered in unit doses suitable for oral administration of fingolimod up to about 0.5 mg/day in total in said pharmaceutical dosage form;

siphonimod, or a pharmaceutically acceptable salt thereof, if present, will be administered in unit doses suitable for oral administration of siphonimod up to about 2 mg/day in total in said pharmaceutical dosage form;

• fonesimod, or a pharmaceutically acceptable salt thereof, if present, will be administered in unit doses suitable for oral administration of fonesimod up to about 10 mg/day in total in said pharmaceutical dosage form; and

• ozanimod, or a pharmaceutically acceptable salt thereof, if present, will be administered in unit doses suitable for oral administration of ozanimod up to about 0.5 mg/day in total in said pharmaceutical dosage form;

• senerimod, or a pharmaceutically acceptable salt thereof, if present, will be administered in unit doses suitable for oral administration of senerimod up to about 2 mg/day in total in said pharmaceutical dosage form;

Ethracemod, or a pharmaceutically acceptable salt thereof, if present, will be administered in unit doses suitable for oral administration of etracimod up to about 1 mg/day in total in said pharmaceutical dosage form;

Amicelimod, or a pharmaceutically acceptable salt thereof, if present, will be administered in unit doses suitable for oral administration of amicelimod up to about 0.2 mg/day in total in said pharmaceutical dosage form.

Said dosage form is particularly intended for once-daily (qd) administration of said unit dose.

47) A further embodiment relates to COMPOUND, or a pharmaceutically acceptable salt thereof, for use according to any one of embodiments 16) to 46), wherein said S1P1 receptor modulator, or a pharmaceutically acceptable salt thereof A possible salt is a dose that is an tolerated effective dose when given as monotherapy (eg as specified in the approval for such S1P1 receptor modulators for the disease or disorder in question when given as monotherapy), or as monotherapy. It will be administered at a dose less than such an acceptable effective dose when given.

48) A further embodiment relates to COMPOUND, or a pharmaceutically acceptable salt thereof, for use according to any one of embodiments 16) to 46), wherein said S1P1 receptor modulator, or a pharmaceutically acceptable salt thereof A possible salt will be administered in a dose that is less than an acceptable effective dose when given as monotherapy (eg, as specified in the approval for such S1P1 receptor modulators for the disease or disorder in question when given as monotherapy).

49) A further embodiment relates to COMPOUND, or a pharmaceutically acceptable salt thereof, for use in combination according to any one of embodiments 16) to 48), wherein COMPOUND is from about 20 mg to about 300 mg (in particular from about 20 mg to about 200 mg; particularly from about 50 mg to about 150 mg) per day in a total dose of COMPOUND that will be administered. In a subembodiment, the total dose is particularly one unit dose per day (qd; for example from about 20 mg qd to about 300 mg qd (in particular from about 20 mg qd to about 200 mg qd; in particular from about 50 mg qd to about 150 mg qd)), or in two separate unit doses per day (bid; for example from about 10 mg bid to about 150 mg bid (particularly from about 10 mg bid to about 100 mg bid; especially from about 25 mg bid to about 75 mg bid)) is given/administered.

In the sub-embodiment of this embodiment 49), the special features of the above embodiments ii) to v) herein are applied with only necessary minor modifications.

50) A further embodiment thus relates to COMPOUND, or a pharmaceutically acceptable salt thereof, for use in combination according to any one of embodiments 16) to 48), wherein COMPOUND is from about 20 mg to 200 mg/day. COMPOUND; in particular about 30 mg to 150 mg/day, about 40 mg to 150 mg/day, about 50 mg to 200 mg, about 50 mg to 150 mg, about 50 mg to 100 mg, or about 100 mg to 200 mg/day COMPOUND; In particular, a total dose of COMPOUND of about 75 mg to 150 mg/day is administered (which will be administered). In a subembodiment, the total dose is given/administered, particularly as one unit dose per day (qd), or as two separate unit doses per day (bid).

Accordingly, the COMPOUND or a pharmaceutically acceptable salt thereof according to the invention is in particular for use in combination (or combination therapy) with said further pharmaceutically active ingredient.

The combined treatment (or combination therapy) may be administered simultaneously (in a fixed dose or in a non-fixed dose), separately, or over a period of time (in particular simultaneously).

"Simultaneously" when referring to a dosage type, means that the dosage type to which it relates in the present application consists in administering two or more active ingredients and/or therapeutic agents at approximately the same time; It is understood that simultaneous administration will result in exposure of the subject to two or more active ingredients and/or therapeutic agents at the same time. In this context, the term "same time" refers in particular to the dosing regimen/periodic which is essentially daily for all active ingredients, i.e. Administration of the two or more active ingredients and/or therapeutic agents occurs at least once on the same day, in particular at approximately the same time on the same day.

When administered simultaneously, the two or more active ingredients may be administered as follows:

ㆍ as a fixed dose combination, or

- in a non-fixed dose combination equivalent to a fixed dose combination (for example using two or more different pharmaceutical compositions to be administered at approximately the same time, preferably by the same route of administration), wherein in particular said ratio - a fixed dose combination will be administered in the same dosing regimen/periodic (eg all active ingredients are administered in particular once a day (qd), or twice a day (bid), etc.), or

- using two or more different routes of administration or dosing regimen/periodicity in a non-fixed dose combination (e.g. one or more of the active ingredients are administered once daily (qd), but at least one other active ingredient is preferably preferably by the same route of administration, in different dosing regimens, such as twice a day (bid), or three times a day (tid), or every other day);

wherein said co-administration results in essentially simultaneous exposure of the subject to pharmaceutically effective amounts of two or more active ingredients and/or therapeutic agents. An example of simultaneous administration of a non-fixed dose combination using two different pharmaceutical compositions to be administered, preferably by the same route of administration, is that COMPOUND is administered once a day (and will be administered ), the S1P1 receptor modulator is a non-fixed dose combination administered (to be administered) once daily. An example of simultaneous administration of a non-fixed dose combination using two different routes of administration or dosing regimen/periodicity is that COMPOUND is (will be administered) administered twice daily and the S1P1 receptor modulator is administered once daily ( to be administered) is a non-fixed dose combination. In another example, COMPOUND is administered (will be administered) once or twice per day, and the S1P1 receptor modulator is administered (will be administered) every other day (wherein such co-administration means that the subject is administered a pharmaceutically effective amount of COMPOUND and It is understood to always result in simultaneous exposure to the S1P1 receptor modulator). COMPOUND will especially be used "simultaneously" when used in combination with an S1P1 receptor modulator.

"Fixed dose combination", when referring to a dosage type, means in the present application one single pharmaceutical composition comprising two or more active ingredients, the dosage type to which it relates, such as in particular the pharmaceutical of any one of embodiments 1) to 15). It means that it consists of administration of an enemy composition.

"Separately", when referring to a type of administration, means that the type of administration to which it relates in the present application consists in the administration of two or more active ingredients and/or therapeutic agents at different times; It is understood that separate administration will result in a treatment period (eg at least 1 h, in particular at least 6 h, in particular at least 12 h) in which the subject is exposed to two or more active ingredients and/or therapeutic agents at the same time; Separate administration may also result in a treatment period in which the subject is exposed to only one of two or more active ingredients and/or therapeutic agents for a certain period of time (eg at least 12 h, in particular at least one day). Separate administration refers in particular to situations in which at least one of the active ingredient and/or therapeutic agent is given at a periodicity substantially different from daily (eg once or twice daily) administration (eg, one active ingredient and/or therapeutic agent). is given, for example, once or twice a day, and another active ingredient and/or therapeutic agent is given, for example, once a week or at even longer intervals).

Administration “over a period of time” refers herein to the sequential administration of two or more active ingredients and/or therapeutic agents at different times. The term particularly refers to a method of administration in which the entire administration of one of the active ingredient(s) and/or therapeutic agent(s) is completed before administration of the other active ingredient(s) and/or therapeutic agent(s) begins. In this way it is possible to administer one of the active ingredient and/or therapeutic agent for several months and then administer the other active ingredient(s) and/or treatment(s).

The term "pharmaceutically effective amount" or "pharmaceutically effective amount" is understood as at least the minimum amount (minimum pharmacologically effective amount) of an active ingredient in question which will result in a pharmacological response in a subject. The pharmacological response may be, for example, that a given active ingredient (at some point during treatment such as for example at T _max or at a trough; especially in the case of an active ingredient intended for continuous administration during the entire treatment period (e.g. (including at the trough))) (in the case of antagonists) in concentrations that block at least 20% (especially at least 50%) of a given biological target. A pharmacological response can also be estimated if a biomarker responsive to blockade of such a given biological target is (significantly) increased/decreased relative to an untreated reference (eg baseline or placebo); Such an increase/decrease may occur at any point during treatment such as, for example, in T _max or at a trough; In the case of active ingredients intended for continuous administration, it can be observed in particular during the entire treatment period (including, for example, at troughs). Preferably, the pharmaceutically effective amount is within the therapeutic dosage range of the active ingredient, which range is generally defined by the range of the least effective dose (MED) to the maximum tolerated dose (MTD).

As used herein, the term “subject” includes a mammal, particularly a human; It refers in particular to a patient, in particular a human patient. Preferably,

• The term refers to a (human) subject at risk/diagnosed as being at risk of developing a particular disease or disorder, and therefore in need of prevention/prevention of such disease or disorder;

• or this term refers to a (human) patient who has been diagnosed with a particular disease or disorder and is therefore in need of treatment of such disease or disorder.

Any related to COMPOUND, or a pharmaceutically acceptable salt thereof, for use in the prevention/prevention or treatment of diseases and disorders in which specific CXCR7 expression or its ligand and S1P both play a role as specifically defined herein; Embodiments are also understood to relate to the following, wherein COMPOUND is administered (intended to be administered) in combination with an S1P1 receptor modulator (in particular a S1P1 receptor modulator as specifically defined in that embodiment).

• such S1P1 receptor modulators, or pharmaceutically acceptable salts thereof, for use in the prevention/prevention or treatment of the above diseases and disorders in which CXCR7 expression or its ligand and S1P both play a role; wherein said S1P1 receptor modulator is administered (intended to be administered) in combination with COMPOUND, or a pharmaceutically acceptable salt thereof;

COMPOUND, or a pharmaceutically acceptable salt thereof, for use in the prevention/prevention or treatment of the above diseases and disorders in which CXCR7 expression or its ligand and S1P both play a role, and such S1P1 receptor modulators, or pharmaceuticals thereof Use of COMPOUND, or a pharmaceutically acceptable salt thereof, for the manufacture of a medicament/pharmaceutical composition comprising a pharmaceutically acceptable salt;

- Pharmaceutical/pharmaceutical comprising COMPOUND, or a pharmaceutically acceptable salt thereof, as an active ingredient, for use in the prevention/prevention or treatment of the above diseases and disorders in which CXCR7 expression or its ligand and S1P both play a role the use of COMPOUND, or a pharmaceutically acceptable salt thereof, for the preparation of a pharmaceutical composition; wherein said medicament/pharmaceutical composition is used (intended for use) in combination with such S1P1 receptor modulator, or a pharmaceutically acceptable salt thereof;

ㆍ As an active ingredient, for use in the prevention/prevention or treatment of the above diseases and disorders in which CXCR7 expression or its ligand and S1P both play a role, comprising the S1P1 receptor modulator, or a pharmaceutically acceptable salt thereof use of such a S1P1 receptor modulator, or a pharmaceutically acceptable salt thereof, for the manufacture of a medicament/pharmaceutical composition comprising: wherein said medicament/pharmaceutical composition is used (intended for use) in combination with COMPOUND, or a pharmaceutically acceptable salt thereof;

COMPOUND, or a pharmaceutically acceptable salt thereof, for the prevention/prevention or treatment of the above diseases and disorders in which CXCR7 expression or its ligand and S1P both play a role, and such S1P1 receptor modulator, or a pharmaceutically thereof use of pharmaceutical compositions comprising acceptable salts;

• A medicament for the prevention/prevention or treatment of the above diseases and disorders in which CXCR7 expression or its ligand and S1P both play a role, the medicament including COMPOUND, or a pharmaceutically acceptable salt thereof; wherein the medicament is administered (which is intended to be administered) in combination with the S1P1 receptor modulator, or a pharmaceutically acceptable salt thereof;

Prevention of the above diseases and disorders in which CXCR7 expression or its ligand and S1P both play a role, comprising administering to a subject (preferably a human) in need thereof an effective amount of COMPOUND, or a pharmaceutically acceptable salt thereof / Method of prevention or treatment, wherein COMPOUND is administered in combination with an effective amount of such a S1P1 receptor modulator, or a pharmaceutically acceptable salt thereof;

CXCR7 expression comprising administering to a subject in need thereof an effective amount of COMPOUND, or a pharmaceutically acceptable salt thereof, and a pharmaceutical composition comprising such S1P1 receptor modulator, or a pharmaceutically acceptable salt thereof; methods of preventing/preventing or treating the above diseases and disorders in which both its ligand and S1P play a role; and

CXCR7 expression or its ligand and both S1P comprising administering to a subject (preferably a human) in need thereof an effective amount of such S1P1 receptor modulator, or a pharmaceutically acceptable salt thereof; A method for preventing/preventing or treating diseases and disorders, wherein the S1P1 receptor modulator is administered in combination with an effective amount of COMPOUND, or a pharmaceutically acceptable salt thereof.

Likewise, any embodiment relating to COMPOUND, or a pharmaceutically acceptable salt thereof, for use in the prophylaxis/prevention or treatment of certain diseases and disorders in which CXCR7 expression or a ligand thereof plays a role is also provided for the specific diseases and disorders Use of COMPOUND, or a pharmaceutically acceptable salt thereof, for prevention/prevention or treatment; And it is understood to refer to a method for preventing/preventing or treating the specific diseases and disorders comprising administering to a subject in need thereof a pharmaceutical composition comprising an effective amount of COMPOUND, or a pharmaceutically acceptable salt thereof.

When the plural form is used for a compound, salt, pharmaceutical composition, disease, etc., it is also intended to mean a single compound, salt, etc.

The definitions provided herein are defined in the composition as defined in any one of embodiments 1) to 50), and, with only minor modifications, the specification and It is intended that the same applies throughout the claims. It is well understood that definitions or preferred definitions of terms may be defined and replaced independently of (and in combination with) any definitions or preferred definitions of any or all other terms as defined herein. .

It is understood that any reference to a compound, suitably and conveniently, also refers to salts (and particularly pharmaceutically acceptable salts) of that compound.

The term "pharmaceutically acceptable salt" refers to a salt that retains the desired biological activity of the subject compound and exhibits minimal undesirable toxicological effects. Such salts include inorganic or organic acid and/or base addition salts depending on the presence of basic and/or acidic groups in the subject compound. See, for example, "Handbook of Pharmaceutical Salts. Properties, Selection and Use.", P. Heinrich Stahl, Camille G. Wermuth (Eds.), Wiley-VCH, 2008; and "Pharmaceutical Salts and Co-crystals", Johan Wouters and Luc Quere (Eds.), RSC Publishing, 2012.

The term "consisting essentially of" means in particular that the composition is in an amount of at least 90% by weight, in particular at least 95% by weight, in particular at least 99% by weight, preferably at least 100% by weight of the composition in the amounts explicitly stated in this embodiment. is understood to mean consisting of (ie, in the sense of “consisting of”). The term “comprising” will preferably be understood in the sense of the term “consisting essentially of”.

The term “essentially” is understood in the context of the present invention to mean in particular that the quantity/purity/time etc in question is at least 90, in particular at least 95, in particular at least 99% of the total amount in question.

For example, when used in the term "essentially simultaneous exposure," the exposure is at least 90, in particular at least 95, in particular at least is understood to mean resulting in simultaneous exposure of a pharmaceutically effective amount of all combination active ingredients for 99%.

For example, when used in a term such as "essentially pure", in the context of the present invention, in particular the composition/compound or the like is in an amount of at least 95% by weight, in particular at least 99% by weight, of the pure composition/compound/crystalline form, etc. is understood to mean that

The term "enantiomerically enriched" in the context of the present invention is particularly intended to mean that at least 90, preferably at least 95, and most preferably at least 99% by weight of COMPOUND are present in the form of enantiomers of COMPOUND. It is understood. COMPOUND is understood to exist in an enantiomerically enriched absolute (3S,4S)-configuration, preferably in an essentially pure absolute (3S,4S)-configuration.

For the avoidance of any doubt, any pharmaceutical composition comprising a pharmaceutically effective amount of COMPOUND may contain additional conventional excipients and/or additives (in appropriate amounts, i.e., said additional conventional ingredients, which may be used alone or in combination) and/or the maximum amount of additives may need to be reduced to make up a total ww% of 100). It is understood that the total amount expressed in “ww%” of a particular composition is 100. The expression “ww%” (or % (w/w)) refers to the weight percentage relative to the total weight of the composition under consideration.

The preparation of the pharmaceutical compositions according to the present invention comprises the combination active ingredients of the present invention, optionally in combination with other therapeutically valuable substances, suitable, non-toxic, inert, pharmaceutically acceptable solid or liquid carrier substances and , can be carried out in a manner familiar to the person skilled in the art by preparing galenic dosage forms, if desired, together with customary pharmaceutical adjuvants (see e.g. RC Rowe, PJ Seskey, SC Owen, Handbook of Pharmaceutical Excipients, 5th edition, Pharmaceutical Press 2006; Remington, The Science and Practice of Pharmacy , 21st Edition (2005), Part 5, "Pharmaceutical Manufacturing" [published by Lippincott Williams & Wilkins]. The pharmaceutical composition for oral administration may in particular be in the form of a capsule or tablet.

A dosage form suitable for enteral administration may be a tablet. Alternatively, a dosage form suitable for enteral administration may be a capsule (particularly a hard gelatin capsule) filled with a pharmaceutical composition comprising an effective amount of COMPOUND. Any type of capsules commonly used to contain pharmaceutical compositions in powder or pellet form, such as hard gelatin capsules, HPMC capsules, and the like can be used in the present invention. Capsules or tablets, optionally in combination with a S1P1 receptor modulator, or a pharmaceutically acceptable salt thereof, as defined herein, in addition to COMPOUND or a pharmaceutically acceptable salt thereof, at least one pharmaceutically acceptable salt Wherever possible, it is understood that inert excipients will be included. As used herein, the term “pharmaceutical composition” is interchangeable with the terms “agent”, “composition” or “medicament”.

Unless used with reference to temperature, the term "about" placed before a numerical value "X" means in this application an interval of from X - 10% of X to X + 10% of X, preferably from X - 5% of X to refers to an interval of X + 5% of X. In the special case of temperature, the term "about" placed before the temperature "Y" means in the present application an interval between temperatures Y - 10 °C and Y + 10 °C, preferably between Y - 5 °C and Y + 5 °C, in particular refers to the interval from Y - 3°C to Y + 3°C. Room temperature means a temperature of about 25°C. When the term n equivalent(s) is used in this application when n refers to a number, it is meant that n refers to approximately the number n, preferably n refers to the exact number n and is within the scope of the present application. .

Whenever the word "between" or "between" is used to describe a numerical range, it will be understood that the endpoint of the stated range is expressly included therein. For example: when a temperature range is described as being between 40°C and 80°C (or between 40°C and 80°C), this means that the endpoints 40°C and 80°C are included in the range; Or, in the case where a variable is defined as an integer between 1 and 4 (or between 1 and 4), this means that the variable is an integer 1, 2, 3, or 4.

Specific embodiments of the invention are illustrated in the following examples, which serve to illustrate the invention in more detail without limiting its scope in any way.

experimental procedure

Abbreviation:

The following abbreviations are used throughout the specification and examples:

b.i.d. (twice a day): also bid; Twice a day

CFA Complete Freund's Adjuvant

CPZ Cuprizone

EAE Experimental Autoimmune Encephalomyelitis

do drawing

h time(s)

IBD inflammatory bowel disease

MOG myelin oligodendrocyte glycoprotein

MS multiple sclerosis

NFL neurofibrillar light chain

ns not paying attention

PLP proteolipid protein

q.d. (once a day): also qd; Once a day

SEM standard error of the mean

Examples of Therapeutic Use of COMPOUND as Monotherapy or in Combination with S1P1 Receptor Modulators

Treatment effects can be modeled in multiple animal models representing diseases and disorders in which CXCR7 expression or its ligand and S1P both play a role.

Example A:

The efficacy of COMPOUND and fingolimod, alone or in combination, can be confirmed, for example, in a mouse model of inflammatory demyelination disease associated with multiple sclerosis (MS).

CXCL12 or CXCL11 plasma concentrations can be determined using methods well known in the art, for example, using the Ella® immunoassay (Bio-Techne®), or the commercial Quantikine ELISA mouse CXCL12/SDF1α kit (available from R&D Systems).

a) Dose discovery experiment in naive mice:

In a pilot experiment, healthy female C57BL/6 mice were orally administered 30 and 100 mg/kg of COMPOUND twice daily (b.i.d.) for 3 days. The objective was to evaluate the dose-effect relationship of COMPOUND on the elevation of CXCL12 in plasma over 24 h in mice of this breed (which is an established biomarker monitoring the pharmacological activity of CXCR7 receptor antagonists).

Based on this experiment, only the highest dose of COMPOUND tested provides COMPOUND plasma exposure at the trough (14 hours after last dose) to sustain plasma CXCL12 increases over 24 h in naive C57BL/6 mice (dose 100 mg/kg, b.i.d.) .

In parallel with the measurement of target binding of COMPOUND, a second pilot experiment is performed. Healthy female C57BL/6 are administered once daily (q.d.) with different doses of fingolimod ranging from 0.01 to 0.3 mg/kg. The objective was to evaluate the dose-effect relationship of fingolimod on lymphocyte counts (which is an established biomarker monitoring the pharmacological activity of S1P1 receptor modulators) in peripheral blood over 24 h in mice of this breed. Based on this experiment, selected doses of fingolimod for combination experiments show some efficacy on lymphocyte count reduction over 24 h (dose 0.03 mg/kg, q.d.).

b) Monotherapy efficacy trials in myelin oligodendrocyte glycoprotein (MOG)-induced experimental autoimmune encephalomyelitis (EAE) model:

The efficacy of COMPOUND in myelin oligodendrocyte glycoprotein (MOG)-induced experimental autoimmune encephalomyelitis (EAE) can be confirmed in a pilot experiment. The objective was to evaluate the dose-effect relationship of COMPOUND on efficacy and plasma CXCL12 increase in a mouse model of MS.

Female C57BL/6 mice are immunized with complete Freund's adjuvant (CFA) and an emulsion of MOG in pertussis toxin (day 0). A total of 150 μg of MOG is injected subcutaneously into each flank of the abdomen at two sites per mouse. Two days after the first injection, mice were injected intraperitoneally with pertussis toxin for a second time (day 2). Within 9 to 14 days, mice show signs of paralysis, which will be graded on a scale of 0 to 5 evaluating the tail and legs as defined as follows: 0 = no clinical signs of EAE, 0.5 = paraplegia of the tail or weak one leg, 1= paraplegia of the tail or weak both legs, 1.5= paralysis of the tail and weak one hindlimb, 2= paraplegia of the tail and partial paralysis of both hind limbs, 2.5= paraplegia of the tail and complete hindlimb paralysis, 2.75= score of 2.5 + unilateral partial hindlimb paralysis, 3=complete bilateral hindlimb paralysis, 3.25=3 + unilateral partial forelimb paralysis, 3.5=3 + unilateral partial forelimb paralysis, 4=complete paralysis (moribunda) and, 5=death or euthanasia.

Disease progression follows a chronic progressive course without remission.

Groups of 9 to 10 mice are orally administered with different doses of COMPOUND starting on the day of disease induction (day 0). It consists of four treatment groups:

1. From vehicle (water) b.i.d., day 0

2. COMPOUND (10 mg/kg) from b.i.d., day 0

3. COMPOUND (30 mg/kg) from b.i.d., day 0

4. COMPOUND (100 mg/kg) from b.i.d., day 0

Clinical scores are assessed daily and disease development is compared between vehicle-treated and COMPOUND-administered mice. A cumulative disease score is calculated by summing all daily clinical scores over the 29-day study period for each mouse. Experiments are terminated on day 29, 1-4 hours post-dose. Plasma samples are taken for confirmation of COMPOUND concentrations and for determination of biomarkers for CXCR7 target binding (CXCL12 levels). CXCL12 plasma concentrations are determined using a commercial Quantikine ELISA mouse CXCL12/SDF1α kit (R&D Systems) according to the manufacturer's instructions.

The results of the efficacy experiments are presented in FIGS. 1-2 . COMPOUND administered in the prophylactic setting shows a dose-dependent efficacy on the overall severity of EAE disease as indicated by a decrease in mean cumulative disease score over the 29-day study ( FIG. 1 ). Efficacy is associated with a dose-dependent increase in plasma CXCL12 levels ( FIG. 2 ).

Based on the pilot experiment, one dose of COMPOUND is selected for the combination efficacy experiment. The selected dose provides COMPOUND plasma exposure at the trough to sustain CXCL12 plasma levels over 24 hours and significantly reduce the overall burden of EAE disease when given in a prophylactic setting (dose: 100 mg/kg, b.i.d.) .

In parallel with the measurement of the dose-dependent efficacy of COMPOUND in the EAE model, a second pilot experiment is performed to evaluate the efficacy of selected doses of fingolimod.

Groups of 10 mice were orally administered starting on the day of disease induction (day 0). It consists of two treatment groups:

1. From vehicle (0.5% methylcellulose/0.5% Tween® 80) b.i.d., day 0

2. fingolimod (0.03 mg/kg) q.d. + from vehicle q.d., day 0

Clinical scores are assessed daily and disease development is compared between vehicle-treated mice and mice administered fingolimod. A cumulative disease score is calculated by summing all daily clinical scores over the 27-day study period for each mouse. The experiment ends on day 27.

Fingolimod administered at a selected dose (0.03 mg/kg) in the prophylactic setting is efficacious for the overall severity of EAE disease as indicated by a decrease in cumulative disease score over the 27-day study ( FIG. 3 ). Efficacy of fingolimod was not associated with an increase in plasma CXCL12 levels.

c) Combination efficacy experiments in MOG-induced EAE model:

Combination efficacy experiments are performed in the same mouse EAE model as described for the pilot experiment.

Groups of 10 mice were orally administered starting immediately before disease onset (day 7). It consists of four treatment groups:

1. From vehicle (0.5% methylcellulose/0.5% Tween® 80) b.i.d., day 7

2. fingolimod (0.03 mg/kg) q.d. + from vehicle q.d., day 7

3. COMPOUND (100 mg/kg) from b.i.d., day 7

4. Fingolimod (0.03 mg/kg) q.d. +　COMPOUND (100 mg/kg) from b.i.d., day 7

Clinical scores are assessed daily and disease development is compared between vehicle-treated mice and mice receiving different treatments. Experiments are terminated on day 16 or day 17. Hematology parameters, including lymphocyte counts, are determined at the end of the experiment. Plasma samples are taken for confirmation of COMPOUND concentration and for determination of biomarkers for CXCR7 target binding (CXCL12 level) and axonal injury (Neurofilament light chain (NFL) level). CXCL12 plasma concentrations are determined using a commercial Quantikine ELISA mouse CXCL12/SDF1α kit (R&D Systems) according to the manufacturer's instructions.

This experiment is suitable to show whether the addition of COMPOUND of a dose showing efficacy and target binding always as a monotherapy in the EAE model shows added benefit to fingolimod of only some effective doses on lymphocyte count.

The results of the combination efficacy experiments are presented in Figures 4-8. Just prior to onset, COMPOUND and fingolimod administered in a therapeutic setting showed moderate and minimal efficacy on clinical score of disease in a mouse EAE model, respectively ( FIG. 4 ). When combined, the two compounds continued to show synergistic efficacy from day 14 in the course of EAE disease, reducing disease severity ( FIGS. 4 and 5 ) and NFL plasma concentrations ( FIG. 6 ); The presence of NFL suggests irreversible/axon damage. These synergistic effects on fingolimod-induced lymphocyte count reduction in peripheral blood ( FIG. 7 ), and COMPOUND-induced increase in CXCL12 plasma levels at the end of the experiment ( FIG. 8 ) cannot be explained by the additive effect of the combination.

1 shows the dose-dependent effect of COMPOUND on the overall severity of EAE disease as assessed by a cumulative disease score defined as the sum of the clinical scores for each mouse over a 29-day study. Mice were treated from Day 0. Data are presented as mean values + SEM; n=9-10/group. *p<0.05, ****p<0.0001 vs. Using vehicle-treated EAE mice, the Kruskal-Wallis test, followed by the Dunns multiple comparison test.

2 shows the dose-dependent effect of COMPOUND on CXCL12 plasma concentrations in a mouse MOG-induced EAE model. Data are presented as mean values + SEM; n = 7-10/group. ****p<0.0001 vs. Using vehicle-treated EAE mice, a one-way ANOVA test, followed by a Dunnett multiple comparison test.

3 shows the effect of fingolimod (0.03 mg/kg, qd) on the overall severity of EAE disease as assessed by a cumulative disease score defined as the sum of the clinical scores for each mouse over a 27-day study. . Mice were treated from Day 0. Data are presented as mean values + SEM; n=10/group. **p<0.01 vs. Vehicle-treated EAE mice, using the Mann Whitney test.

4 shows the therapeutic efficacy of COMPOUND, fingolimod, and combinations thereof on mean clinical score in an EAE mouse model. Mice were treated from Day 7 to the end of the study. Data are presented as mean values + SEM; n=10/group. *p<0.05, **p<0.01 vs. Using vehicle-treated EAE mice, the Kruskal-Wallis test, followed by the Dunns multiple comparison test.

5 shows the therapeutic effect of COMPOUND, fingolimod, and combinations thereof on the severity of EAE disease in mice presented as the maximum clinical score reached over a 16-day study. Data are presented as mean values + SEM; n = 10/group. *p<0.05, **p<0.01, using Kruskal-Wallis test, followed by an uncorrected Dunn's multiple comparison test.

6 shows the therapeutic effect of COMPOUND, fingolimod, and combinations thereof on neurofilament light chain plasma concentrations in a mouse EAE model. Data are presented as mean values + SEM; n = 8-9/group. *p<0.05, **p<0.01, using a one-way ANOVA test followed by an unadjusted Fisher LSD multiple comparison test.

7 shows the effect of COMPOUND, fingolimod, and combinations thereof on blood lymphocyte count in a mouse EAE model. Data are presented as mean values + SEM; n = 8-10/group. **p<0.01 vs. Using vehicle-treated EAE mice, a one-way ANOVA test followed by an uncorrected Fisher LSD multiple comparison test.

8 shows the effect of COMPOUND, fingolimod, and combinations thereof on plasma CXCL12 concentrations in a mouse EAE model. Data are presented as mean values + SEM; n = 8-10/group. ****p<0.0001, using a one-way ANOVA test followed by an uncorrected Fisher LSD multiple comparison test.

Example B:

Experiment 1): The direct effect of COMPOUND on myelination can be confirmed in a cuprizone-induced demyelination mouse model, and primary demyelination is not immune-mediated.

Male C57BL/6 mice were treated with Cuprizone (CPZ; 150 mg/kg, b.i.d.), a chopper chelating agent that causes death of mature oligodendrocytes, by oral gavage twice a day for 6 weeks. exposed while COMPOUND (100 mg/kg, b.i.d.) in a prophylactic setting, ie, co-administered with cuprizone from day 0 (COMPOUND prev-CPZ); or in a therapeutic setting, ie, starting 3 weeks after initiation of cuprizone exposure until the end of the study (COMPOUND ther-CPZ).

Experiments are terminated after 6 weeks of cuprizone exposure. Plasma samples are taken for confirmation of COMPOUND concentrations and for determination of biomarkers for CXCR7 target binding (CXCL12 levels). CXCL12 plasma concentrations are determined as detailed in Example A. Brain samples are isolated and fixed for histopathology and immunohistochemical examination to assess the extent of demyelination (Luxol Fast Blue for myelin staining) and loss of mature oligodendrocytes (GSTπ staining).

The results of this study are presented in Figures 9-10. After 6 weeks of exposure, cuprizone induced significant demyelination ( FIG. 9 ) and significant loss of mature oligodendrocytes ( FIG. 10 ). While cuprizone was still administered, both COMPOUND treatment regimens (Prophylactic: COMPOUND prev-CPZ and Therapeutic: COMPOUND ther-CPZ) resulted in myelin staining in the corpus callosum ( FIG. 9 ) and mature oligodendrocyte counts ( FIG. 10 ). was significantly increased.

FIG. 9 shows cuprizone with the same formulation starting on Day 0 (COMPOUND prev-CPZ) or 3 weeks after cuprizone exposure (COMPOUND ther-CPZ) for demyelination in a mouse cuprizone-induced demyelination model. shows the effect of COMPOUND administered concurrently with Parietal coronal sections were stained with Luxol Fast Blue, and the intensity of intracorporal staining was quantified using Orbit image analysis software. Results are expressed as mean + SEM; n=7-8 mice/group. *p<0.05, **p<0.01, ****p<0.0001, vs. Using vehicle-treated CPZ mice (CPZ), one-way ANOVA followed by uncorrected Fisher multiple comparison test.

10 shows the number of mature oligodendrocytes in a mouse cuprizone-induced demyelination model, starting on Day 0 (COMPOUND prev-CPZ) or starting at 3 weeks after cuprizone exposure (COMPOUND ther-CPZ). It shows the effect of COMPOUND co-administered with Cuprizone as a formulation. The parietal coronal sections were stained with GSTπ, and quantitative analysis in the corpus callosum was quantified using Orbit image analysis software. Results are the average number of cells normalized by the selected area of interest (mm ² ). + expressed as SEM; n=6-8 mice/group. *p<0.05, **p<0.01, ****p<0.0001, vs. Using vehicle-treated CPZ mice (CPZ), one-way ANOVA followed by an uncorrected Fisher multiple comparison test.

Experiment 2): In the second experiment, the therapeutic effect of COMPOUND on myelination was confirmed in a model of cuprizone-induced toxic demyelination, in which spontaneous remyelination occurs after cuprizone withdrawal.

Male C57BL/6 mice were exposed to a 0.2% cuprizone diet for 6 weeks, then switched to a control diet for an additional week of exposure. Groups of 8-9 mice are administered orally starting after 5 weeks of cuprizone exposure. It consists of three treatment groups:

1. Vehicle (0.5% methylcellulose/0.5% Tween® 80) b.i.d., week 5 to week 7

2. fingolimod (0.3 mg/kg) q.d. + vehicle q.d., from week 5 to week 7

3. COMPOUND (100 mg/kg) b.i.d., from week 5 to week 7

The trial is terminated after 2 weeks of treatment (week 7), meaning 1 week after cuprizone withdrawal. Hematology parameters including lymphocyte count are measured at the end of the experiment, 1 hour after the last dose. Plasma samples are taken for confirmation of COMPOUND concentrations and for determination of biomarkers for CXCR7 target binding (CXCL12 levels). Brain samples are isolated and fixed for histopathology and immunohistochemistry to assess the extent of demyelination (Luxol Fast Blue for myelin staining).

This experiment was conducted with a COMPOUND of a dose showing efficacy and always target binding as a monotherapy in both the EAE model and the cuprizone model - a dose of fingolimod (dose: 0.3 mg/kg) completely effective against lymphocyte count reduction over 24 hours. , q.d.) is suitable for head-on comparison.

The results of this study are presented in FIG. 11 . After 6 weeks of cuprizone exposure followed by 1 week of control food, vehicle-treated mice showed significant demyelination in the corpus callosum. One week after CPZ withdrawal, COMPOUND significantly accelerated spontaneous remyelination, whereas fingolimod had no effect ( FIG. 11 ).

11 shows the therapeutic effect of COMPOUND and fingolimod starting 1 week before cuprizone withdrawal on demyelination/remyelination in a mouse cuprizone-induced demyelination model. Parietal coronal sections were stained with Luxol Fast Blue, and the intensity of intracorporal staining was quantified using Orbit image analysis software. Results are expressed as mean + SEM; n=7-8 mice/group. * p<0.05, **** p<0.0001, vs. Using vehicle-treated CPZ mice (CPZ), one-way ANOVA followed by an uncorrected Fisher multiple comparison test.

Example C:

The therapeutic efficacy of COMPOUND and siphonimod alone or in combination can be confirmed in a mouse model of inflammatory demyelination disease.

a) Dose discovery experiments in healthy mice:

In a pilot experiment, healthy female SJL/J mice are administered orally once daily with different doses of siphonimod ranging from 0.03 to 1 mg/kg for 2-3 days. The objective was to evaluate the dose-effect relationship of siphonimod on lymphocyte counts (which is an established biomarker monitoring the pharmacological activity of S1P1 receptor modulators) in peripheral blood over 24 h in mice of this breed. Based on this experiment, the selected dose of siphonimod for the combination experiment shows full efficacy on lymphocyte count reduction over 24 h (dose 0.3 mg/kg, q.d.). siphonimod at the selected dose and 100 mg/kg, b.i.d. The combination of COMPOUND of COMPOUND has no effect on each other's biomarkers, namely lymphopenia and plasma CXCL12 increase, respectively, nor on their respective plasma pharmacokinetics.

b) Monotherapy Efficacy Study in Proteolipid Protein (PLP)-Induced EAE Model:

The therapeutic efficacy of COMPOUND in PLP-induced EAE can be confirmed in a pilot experiment. The objective was to evaluate the dose-effect relationship of COMPOUND on the increase in efficacy and both plasma CXCL11 and CXCL12.

Female SJL/J mice are immunized with an emulsion of CFA and PLP in pertussis toxin (day 0). A total of 100 μg of PLP is injected subcutaneously into each flank of the abdomen at two sites per mouse. Two days after the first injection, mice were injected intraperitoneally with pertussis toxin for a second time (day 2). Within 9 to 16 days, mice will show signs of paralysis, which will be graded on a scale of 0 to 5 evaluating the tail and legs as defined as follows: 0 = no clinical signs of EAE, 0.5 = paraplegia of the tail or weak one leg, 1= paraplegia of the tail or weak two legs, 1.5= paralysis of the tail and weak one hindlimb, 2= paraplegia of the tail and partial paralysis of both hind limbs, 2.5= paraplegia of the tail and complete hindlimb paralysis, 2.75= score of 2.5 + unilateral partial hindlimb paralysis, 3=complete bilateral hindlimb paralysis, 3.25=3 + unilateral partial forelimb paralysis, 3.5=3 + unilateral partial forelimb paralysis, 4=complete paralysis (moribunda) and, 5=death or euthanasia. Disease progression follows a relapse-remission process, with a first peak of disease 3-5 days after onset, followed by a period of remission and a second peak of disease between 20-30 days after EAE induction.

Groups of 14 to 16 mice are orally administered different doses of COMPOUND starting from the first sign of disease for each mouse. The study consists of four treatment groups:

1. Vehicle (water) b.i.d., from disease onset for each mouse

2. COMPOUND (10 mg/kg) b.i.d., from disease onset for each mouse

3. COMPOUND (100 mg/kg) b.i.d., from disease onset for each mouse

4. COMPOUND (150 mg/kg) b.i.d., from disease onset for each mouse

Clinical scores are assessed daily in a blinded fashion and disease development is compared between vehicle-treated and COMPOUND-administered mice. A cumulative disease score is calculated by summing all daily clinical scores over 30-days after initiation of treatment for each mouse. Experiments are terminated after 30-33 days of COMPOUND treatment, meaning between 42-48 days after EAE induction, based on the day of mouse enrollment. Plasma samples are taken for confirmation of COMPOUND concentrations and for determination of biomarkers for CXCR7 target binding (CXCL11 and CXCL12 levels). CXCL12 plasma concentrations are determined as detailed in Example A.

The results of the efficacy experiments are presented in FIG. 12 . COMPOUND administered in the therapeutic setting shows a dose-dependent efficacy on overall severity of disease as indicated by a significant decrease in mean cumulative disease score ( FIG. 12 ). Efficacy is associated with a dose-dependent increase in plasma CXCL11 and CXCL12 levels ( FIG. 13 ).

12 shows the dose-dependent effect of COMPOUND on the overall severity of EAE disease as assessed by the cumulative disease score, defined as the sum of the clinical scores for each mouse over 30-days after initiation of treatment. Mice were treated individually, starting at the first sign of disease. Data are presented as mean values + SEM; n=14-16/group. *p<0.05 vs. Using vehicle-treated EAE mice, the Kruskal-Wallis test, followed by an uncorrected Dunn's multiple comparison test.

13 shows a dose-dependent effect of COMPOUND on plasma CXCL12 concentrations in a mouse PLP-induced EAE model. Data are presented as mean values + SEM; n = 13-14/group. ****p<0.0001, using a one-way ANOVA test followed by an uncorrected Fisher LSD multiple comparison test.

Based on the above pilot experiment, one dose of COMPOUND (dose: 100 mg/kg, b.i.d.) is selected for the combination efficacy experiment. The selected dose increases CXCL11 and CXCL12 plasma levels at the trough and maximally decreases the clinical score in the PLP-induced EAE model.

c) Combination efficacy experiments in a PLP-induced EAE model:

Combination efficacy experiments are performed in the same mouse EAE model as described for the pilot experiment.

Groups of 10-15 mice are administered orally starting at disease onset for each mouse. The study consists of four treatment groups:

1. Vehicle (0.5% Methylcellulose/0.5% Tween® 80) b.i.d., from EAE onset

2. siphonimod (0.3 mg/kg) q.d. + vehicle q.d., from the onset of EAE

3. COMPOUND (100 mg/kg) b.i.d., from the onset of EAE

4. siphonimod (0.3 mg/kg) q.d. +　COMPOUND (100 mg/kg) b.i.d., from the onset of EAE

Clinical scores are assessed daily in a blinded fashion, and disease development is compared between vehicle-treated mice and mice receiving different treatments and between combination and monotherapy treatments. In parallel, the mice's weights are recorded daily to monitor their general health. Experiments are terminated after at least 30 days of COMPOUND treatment for each mouse. S1P1 and CXCR7 target binding, ie, lymphocyte count and CXCL11 and CXCL12 plasma levels, respectively, are measured at the end of the experiment. Plasma samples are also taken to confirm COMPOUND and siphonimod concentrations.

Example D: Study of safety, tolerability, pharmacokinetics and pharmacodynamics of COMPOUND can be confirmed after single dose in healthy male subjects

A) Study Design (ClinicalTrials.gov: NCT03869320)

Six dose levels, COMPOUND of 1, 3, 10, 30, 100, and 200 mg are studied in a randomized, double-blind, placebo-controlled, first-in-human study. In each dose level group, 6 healthy male subjects receive COMPOUND and 2 healthy male subjects receive a similar placebo orally in the morning under fasting conditions. Subjects were monitored for 14 days after each administration to determine (i) tolerability and safety (adverse events, vital signs, clinical laboratory, ECG), (ii) pharmacokinetics (COMPOUND concentration in plasma), and (iii) pharmacodynamics (plasma CXCL11). and CXCL12). The effect of food is further investigated by administering the same treatment to the same subject after a standardized high-fat breakfast in the 30 mg dose level group. Substance balance and ADME are further investigated by administering an oral COMPOUND microtracer or similar placebo with the assigned treatment in the 100 mg dose level group. 200 mg dose level group i.v. with assigned treatment Absolute bioavailability is further investigated by administering a COMPOUND microtracer or similar placebo.

result:

COMPOUND is safe and well tolerated over the entire range of single, oral doses of 1 to 200 mg. At a dose ≥10 mg, t _max ranges from 1.3 to 3.0 h, and terminal t _1/2 ranges from 17.8 to 23.6 h. The increase in exposure over the dose range is essentially dose-proportional and there is no associated food effect on pharmacokinetics. COMPOUND was found to be excreted primarily in the feces in this study and to a lesser extent in the urine. The absolute bioavailability was about 50%.

Plasma concentrations of the target binding biomarker CXCL12 increase in a dose-dependent manner over the tested dose range to approximately 2-fold higher levels when compared to baseline. Plasma CXC12 concentrations and fold changes compared to baseline are similar after administration of 100 mg and 200 mg COMPOUND ( FIG. 14 ). An indirect-response pharmacokinetic/pharmacodynamic model predicting exposure-response at steady state well explains the relationship between COMPOUND and CXCL12 concentration ( FIG. 15 ). In healthy volunteers in this study, CXCL11 concentrations remained essentially unchanged.

14 shows the dose-response relationship of peak CXCL12 plasma concentrations in healthy subjects in the study. Data are presented as fold change compared to baseline, horizontal lines represent mean and dots represent individual data points.

15 shows the predicted exposure response relationship at steady state stratified by dose. Dots represent median predicted fold change compared to baseline, and error bars represent 80% prediction intervals.

Example E: Study of safety, tolerability, pharmacokinetics and pharmacodynamics of COMPOUND can be confirmed after multiple doses in healthy male and female subjects

A) Study Design (ClinicalTrials.gov: NCT04286750)

In a randomized, double-blind, placebo-controlled study, different dose levels, eg, COMPOUND of 30, 100, and 200 mg, are studied. In each dose level group, 8 healthy subjects (4 males and 4 females) received COMPOUND and 2 healthy subjects (1 male and 1 female) received a similar placebo in fasting conditions. It is administered orally once a day for 7 days, eg in the morning. Subjects were monitored for 7 days of dosing until 8 days after the last dose to determine (i) tolerability and safety (adverse events, vital signs, clinical laboratory, ECG), (ii) pharmacokinetics (COMPOUND concentration in plasma), and (iii) Pharmacodynamics (including for example plasma levels of CXCL11 and CXCL12) are investigated.

Claims (15)

As an active ingredient,
- (3S,4S)-1-Cyclopropylmethyl-4-{[5-(2,4-difluoro-phenyl)-isoxazole-3-carbonyl]-amino}-piperidine-3-carboxylic acid (1-Pyrimidin-2-yl-cyclopropyl)-amide:

,
or a pharmaceutically acceptable salt thereof.
ㆍ In combination with an S1P1 receptor modulator, or a pharmaceutically acceptable salt thereof,
as well as a pharmaceutical composition comprising at least one pharmaceutically acceptable excipient. According to claim 1, wherein the S1P1 receptor modulator is fingolimod, ponesimod, siphonimod, ozanimod, senerimod, or etrasimod; Or a pharmaceutically acceptable salt thereof, a pharmaceutical composition. 3. The S1P1 receptor modulator of claim 1 or 2, wherein the S1P1 receptor modulator, or a pharmaceutically acceptable salt thereof, is or is less than an tolerated effective dose of the S1P1 receptor modulator when given as monotherapy. A pharmaceutical composition comprising a dose of an S1P1 receptor modulator. (3S,4S)-1-cyclopropylmethyl-4-{[5-(2,4-) for combined use in the prophylaxis or treatment of an autoimmune or inflammatory disease or disorder, transplant rejection, or a neurodegenerative disease or disorder Difluoro-phenyl)-isoxazole-3-carbonyl]-amino}-piperidine-3-carboxylic acid (1-pyrimidin-2-yl-cyclopropyl)-amide, or a pharmaceutically acceptable salt thereof (3S,4S)-1-cyclopropylmethyl-4-{[5-(2,4-difluoro -Phenyl)-isoxazole-3-carbonyl]-amino}-piperidine-3-carboxylic acid (1-pyrimidin-2-yl-cyclopropyl)-amide. (3S,4S)-1-cyclopropylmethyl-4-{[5-(2,4-difluoro-phenyl) for combination use according to claim 4, wherein the use is for the prophylaxis or treatment of )-Isoxazole-3-carbonyl]-amino}-piperidine-3-carboxylic acid (1-pyrimidin-2-yl-cyclopropyl)-amide, or a pharmaceutically acceptable salt thereof:
• autoimmune and/or inflammatory diseases and disorders; wherein the disease or disorder is
> Multiple Sclerosis (MS); idiopathic inflammatory demyelination disease; optic neuromyelitis spectrum disorders including optic neuromyelitis and acute optic neuritis; autoimmune encephalomyelitis, including acute disseminated encephalomyelitis (ADEM) and multiphase disseminated encephalomyelitis (MDEM); myelitis, including transverse myelitis spectrum disorders, acute flaccid myelitis, gray myelitis, leukomyelitis, and meningococcal myelitis; brainstem encephalitis; anti-myelin oligodendrocyte glycoprotein (anti-MOG) associated diseases, including anti-MOG encephalomyelitis; Guillain-Barré Syndrome; chronic inflammatory demyelinizing polyneuropathy (CIDP); and an autoimmune and/or inflammatory demyelination disease or disorder selected from anti-myelin-associated glycoprotein (anti-MAG) peripheral neuropathy;
> rheumatoid arthritis (RA);
> inflammatory bowel disease (IBD) including Crohn's disease or ulcerative colitis;
> systemic lupus erythematosus (SLE), including lupus nephritis and neuropsychiatric systemic lupus erythematosus;
> interstitial cystitis;
> celiac disease;
>osteoarthritis;
>psoriasis;
> Type I diabetes;
> Ankylosing spondylitis; or
> A strong viral infection, including COVID-19, or cytokine release syndrome followed by acute respiratory distress syndrome;
• transplant rejection; wherein said transplant rejection is in particular rejection of a transplanted organ such as kidney, liver, heart, lung, pancreas, cornea, or skin; graft versus host disease caused by hematopoietic stem cell transplantation; chronic allograft rejection and chronic allograft angiopathy; or
• neurodegenerative diseases and disorders; wherein said neurodegenerative disease and disorder is, inter alia, amyotrophic lateral sclerosis (ALS), Huntington's disease, Alzheimer's disease (AD), Parkinson's disease (PD), or adrenal leukodystrophy. (3S,4S)-1-cyclopropylmethyl-4-{[5- (2,4-Difluoro-phenyl)-isoxazole-3-carbonyl]-amino}-piperidine-3-carboxylic acid (1-pyrimidin-2-yl-cyclopropyl)-amide, or a pharmaceutical thereof commercially acceptable salts. 7. Combination use according to claim 6, wherein the use is for the treatment of a patient diagnosed with an autoimmune and/or inflammatory disease or disorder, wherein the treatment reduces the rate of progression of the autoimmune and/or inflammatory disease or disorder. (3S,4S)-1-Cyclopropylmethyl-4-{[5-(2,4-difluoro-phenyl)-isoxazole-3-carbonyl]-amino}-piperidine-3-carboxylic acid for (1-Pyrimidin-2-yl-cyclopropyl)-amide, or a pharmaceutically acceptable salt thereof. 8. The method of claim 7, wherein the autoimmune and/or inflammatory disease or disorder is
• Multiple Sclerosis (MS); idiopathic inflammatory demyelination disease; autoimmune encephalomyelitis, including acute disseminated encephalomyelitis (ADEM) and multiphase disseminated encephalomyelitis (MDEM); myelitis, including transverse myelitis spectrum disorders, acute flaccid myelitis, gray myelitis, leukomyelitis, and meningococcal myelitis; brainstem encephalitis; Guillain-Barré Syndrome; chronic inflammatory demyelinizing polyneuropathy (CIDP); anti-myelin-associated glycoprotein (anti-MAG) peripheral neuropathy; and myelin oligodendrocyte glycoprotein (MOG)-antibody-associated disease or disorder;
• inflammatory bowel diseases selected in particular from Crohn's disease and ulcerative colitis; or
ㆍ Systemic lupus erythematosus (SLE)
Phosphorus, (3S,4S)-1-Cyclopropylmethyl-4-{[5-(2,4-difluoro-phenyl)-isoxazole-3-carbonyl]-amino}-piperi for combination use Dean-3-carboxylic acid (1-pyrimidin-2-yl-cyclopropyl)-amide, or a pharmaceutically acceptable salt thereof. (3S,4S)-1-cyclopropylmethyl-4-{[5 for combination use according to claim 4, wherein the use is for the prevention or treatment of an autoimmune and/or inflammatory demyelination disease or disorder. -(2,4-Difluoro-phenyl)-isoxazole-3-carbonyl]-amino}-piperidine-3-carboxylic acid (1-pyrimidin-2-yl-cyclopropyl)-amide, or its A pharmaceutically acceptable salt. (3S,4S)-1-cyclopropylmethyl-4-{[5-(2,4-difluoro-phenyl)-isoxazole for combined use according to claim 9, wherein the use is for -3-carbonyl]-amino}-piperidine-3-carboxylic acid (1-pyrimidin-2-yl-cyclopropyl)-amide, or a pharmaceutically acceptable salt thereof
> for the treatment of a patient diagnosed with MS, wherein the treatment comprises
o reduce the rate of progression of MS;
o improve the symptoms of MS;
o reduce the rate of demyelination;
o reduce the rate of irreversible neurodegenerative damage such as axonal damage;
o have an effect of remyelination;
o Reduce the rate of brain atrophy/cerebral atrophy; or
> for the prophylaxis of MS, wherein the prophylaxis of MS comprises delaying the onset of MS in a subject at risk of, or diagnosed with, developing MS; Said subject is in particular a subject who has experienced clinical solitary syndrome (CIS) or has been diagnosed as having experienced CIS. 11. The method according to any one of claims 4 to 10, wherein the S1P1 receptor modulator is selected from fingolimod, ponesimod, siphonimod, ozanimod, senerimod, or etrasimod; (3S,4S)-1-cyclopropylmethyl-4-{[5-(2,4-difluoro-phenyl)-isoxazole-3-carbonyl for combination use, or a pharmaceutically acceptable salt thereof, ]-Amino}-piperidine-3-carboxylic acid (1-pyrimidin-2-yl-cyclopropyl)-amide, or a pharmaceutically acceptable salt thereof. 12. The method of claim 11, wherein the S1P1 receptor modulator, or a pharmaceutically acceptable salt thereof, will be administered in a pharmaceutical dosage form suitable for oral administration of the S1P1 receptor modulator,
Fingolimod, or a pharmaceutically acceptable salt thereof, if present, will be administered in unit doses suitable for oral administration of fingolimod up to about 0.5 mg/day in total in said pharmaceutical dosage form;
siphonimod, or a pharmaceutically acceptable salt thereof, if present, will be administered in unit doses suitable for oral administration of siphonimod up to about 2 mg/day in total in said pharmaceutical dosage form;
• fonesimod, or a pharmaceutically acceptable salt thereof, if present, will be administered in unit doses suitable for oral administration of fonesimod up to about 20 mg/day in total in said pharmaceutical dosage form; and
• ozanimod, or a pharmaceutically acceptable salt thereof, if present, will be administered in unit doses suitable for oral administration of ozanimod up to about 1 mg/day in total in said pharmaceutical dosage form;
• senerimod, or a pharmaceutically acceptable salt thereof, if present, will be administered in unit doses suitable for oral administration of senerimod up to about 4 mg/day in total in said pharmaceutical dosage form; and
Ethracemod, or a pharmaceutically acceptable salt thereof, if present, will be administered in a unit dose suitable for oral administration of etracimod up to about 2 mg/day in total in said pharmaceutical dosage form;
(3S,4S)-1-Cyclopropylmethyl-4-{[5-(2,4-difluoro-phenyl)-isoxazole-3-carbonyl]-amino}-piperidine- for combination use 3-carboxylic acid (1-pyrimidin-2-yl-cyclopropyl)-amide, or a pharmaceutically acceptable salt thereof. 13. The dose according to any one of claims 4 to 12, wherein the S1P1 receptor modulator, or a pharmaceutically acceptable salt thereof, is an effective dose tolerated when given as monotherapy; or (3S,4S)-1-cyclopropylmethyl-4-{[5-(2,4-difluoro Rho-phenyl)-isoxazole-3-carbonyl]-amino}-piperidine-3-carboxylic acid (1-pyrimidin-2-yl-cyclopropyl)-amide, or a pharmaceutically acceptable salt thereof. S1P1 receptor modulator, which is fingolimod, ponesimod, siphonimod, ozanimod, senerimod, or etrasimod for use in combination as defined in any one of claims 4 to 13; Or a pharmaceutically acceptable salt thereof, wherein the S1P1 receptor modulator is (3S,4S)-1-cyclopropylmethyl-4-{[5-(2,4-difluoro-phenyl)-isoxazole-3 S1P1, which is intended to be administered in combination with -carbonyl]-amino}-piperidine-3-carboxylic acid (1-pyrimidin-2-yl-cyclopropyl)-amide, or a pharmaceutically acceptable salt thereof. A receptor modulator, or a pharmaceutically acceptable salt thereof. A method for preventing or treating an autoimmune or inflammatory disease or disorder, transplant rejection, or a neurodegenerative disease or disorder, the method comprising: a pharmaceutically effective amount of (3S,4S)-1-cyclopropylmethyl-4-{[5-( 2,4-Difluoro-phenyl)-isoxazole-3-carbonyl]-amino}-piperidine-3-carboxylic acid (1-pyrimidin-2-yl-cyclopropyl)-amide, or a pharmaceutical thereof (3S,4S)-1-cyclopropylmethyl-4-{[5-(2,4-difluoro-phenyl)-isoxazole- 3-carbonyl]-amino}-piperidine-3-carboxylic acid (1-pyrimidin-2-yl-cyclopropyl)-amide administered in combination with an S1P1 receptor modulator, or a pharmaceutically acceptable salt thereof how to be

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